1. Central Nervous System
The central nervous system is a bilateral and essentially symmetrical structure with seven main parts: the spinal cord, medulla oblongata, pons, cerebellum, midbrain, diencephalon, and the cerebral hemispheres. FIG. 1 shows a lateral view of the human brain from Stedman's Medical Dictionary, 27th Edition, plate 7 at A7 (2000).
The spinal cord, the most caudal part of the central nervous system, receives and processes sensory information from the skin, joints, and muscles of the limbs and trunk and controls movement of the limbs and the trunk. It is subdivided into cervical, thoracic, lumbar and sacral regions. The spinal cord continues rostrally as the brainstem, which consists of the medulla, pons, and midbrain. The brainstem receives sensory information from the skin and muscles of the head and provides the motor control for the muscles of the head. It also conveys information from the spinal cord to the brain and from the brain to the spinal cord, and regulates levels of arousal and awareness through the reticular formation. The brainstem contains several collections of cell bodies, the cranial nerve nuclei. Some of these receive information from the skin and muscles of the head; others control motor output to muscles of the face, neck and eyes. Still others are specialized for information from the special senses: hearing, balance and taste. (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The medulla oblongata, which lies directly rostral to the spinal cord, includes several centers responsible for vital autonomic functions, such as digestion, breathing and the control of heart rate (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The pons, which lies rostral to the medulla, conveys information about movement from the cerebral hemispheres to the cerebellum (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The cerebellum lies behind the pons and is connected to the brain stem by several major fiber tracts called peduncles. The cerebellum modulates the force and range of movement, and is involved in the learning of motor skills. It also contributes to learning and cognition (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The midbrain, which lies rostral to the pons, controls many sensory and motor functions, including eye movements and the coordination of visual and auditory reflexes (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The diencephalon lies rostral to the midbrain and contains two structures. One, the thalamus, processes most of the information reaching the cerebral cortex from the rest of the central nervous system and is involved in other functions including motor control, autonomic function and cognition. The other, the hypothalamus, regulates autonomic, endocrine, and visceral function (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The cerebral hemispheres consist of a heavily wrinkled outer layer, the cerebral cortex, and deep-lying gray-matter structures—the basal ganglia, which participate in regulating motor performance; the hippocampus, which is involved with aspects of learning and memory storage; and the amygdaloid nuclei, which coordinate the autonomic and endocrine responses of emotional states (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
The cerebral cortex is divided into four lobes: the frontal lobe, parietal lobe, temporal lobe and occipital lobe. The surfaces of the cerebral hemispheres contain many grooves or furrows, known as fissures and sulci. The portions of brain lying between these grooves are called convolutions or gyri. The lateral cerebral fissure (fissure of Sylvius) separates the temporal from the frontal lobe. The central sulcus (Rolandic sulcus) separates the frontal from the parietal lobe (Kandel, E. et al., Principles of Neural Science, 4th Ed., p. 8, 2000).
1.1. Meninges of the Brain, Spinal Cord and their Spaces
The meninges, three distinct connective tissue membranes that enclose and protect the brain and spinal cord, are named (from outer to inner layer) the dura mater, the arachnoid, and the pia mater. FIG. 2 shows an illustrative sagittal view of the human brain (J. G. Chusid, Correlative Neuroanatomy & Functional Neurology, 18th Ed., p. 46, 1982). The meninges are associated with three spaces or potential spaces: the epidural potential space, subdural potential space and the subarachnoid space. FIG. 3 is a drawing of a cross section of the three meningeal layers that cover the brain and the sub-arachnoid space (SAS) between the outer cellular layer of the arachnoid and pia mater. (Haines, D. E., Anatomical Record 230: 3-21, 1991). FIG. 4 is a schematic drawing depicting the meninges and their spaces surrounding the spinal cord. (Kulkarni, N. V., “Clinical anatomy for students: problem solving approach,” Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, p. 348-349 (2006)).
The epidural space is a physiological space in the spinal cord; it is not normally present in the brain, but it can develop in response to arterial bleeding, resulting in accumulation of blood between the skull and the dura mater (extradural hemorrhage or epidural hematoma). (Schuenke, M. et al., “Thieme Atlas of Anatomy: Head and Neuroanatomy,” Georg Thieme Verlag, Germany, p. 191 (2007); Stedman's Medical Dictionary, Lippincott, Williams & Wilkins, 27th Ed. (2000)). In the spinal cord, the epidural space refers to the space between the dura mater and the lining of the vertebral canal. The spinal epidural space contains loose areolar tissue, internal vertebral venous plexus, roots of spinal nerves, spinal branches of regional arteries, recurrent meningeal branches of spinal nerves and semi fluid fat. Anesthetic agents are commonly administered in the epidural space for pain management associated with surgical procedures to numb the spinal nerves that traverse the space. (Kulkarni, N. V., “Clinical anatomy for students: problem solving approach,” Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, p. 348-349 (2006)).
The subdural space refers to the potential space that extends from the dura mater to the arachnoid. It can develop as a result of extravasation of blood from bridging veins that artificially open the subdural space between the meningeal layer of the dura mater and the upper layer of the arachnoid membrane (subdural hematoma or subdural hemorrhage). (Schuenke, M. et al., “Thieme Atlas of Anatomy: Head and Neuroanatomy,” Georg Thieme Verlag, Germany, p. 191 (2007); Stedman's Medical Dictionary, Lippincott, Williams & Wilkins, 27th Ed. (2000)).
The subarachnoid space (SAS) or subarachnoid cavity refers to the physiologically normal space that lies between the arachnoid and pia mater. It is filled with cerebrospinal fluid (CSF) and is traversed by blood vessels. (See section titled 1.1.3. “Subarachnoid Cavity” and “Subarachnoid Cisternae”). Spontaneous bleeding into the subarachnoid space (subarachnoid hemorrhage) is usually as a result of arterial bleeding from an aneurysm, although it can occur due to trauma as well. (See section 3 below titled “Subarachnoid hemorrhage”). The subarachnoid space in the spinal cord is of uniform size up to the lower end of the spinal cord beyond which it expands. (Kulkarni, N. V., “Clinical anatomy for students: problem solving approach,” Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, p. 348-349 (2006)).
1.1.1. Dura Mater
The dura mater sends inward four processes that divide the cavity of the skull into a series of freely communicating compartments and further provides for the protection of the different parts of the brain. The dura mater is a dense fibrous structure that covers the brain and spinal cord. It has an inner meningeal and an outer periosteal or endosteal layer. The dural layers over the brain generally are fused, except where they separate to provide space for the venous sinuses and where the inner layer forms septa between brain portions. The outer layer attaches firmly to the inner surface of the cranial bones and sends vascular and fibrous extensions into the bone itself. Around the margin of the foramen magnum (the large opening in the base of the skull forming the passage from the cranial cavity to the spinal cavity) it is closely adherent to the bone, and is continuous with the spinal dura mater.
The cranial dura mater consists of fibroblasts, abundant extracellular collagen and a few elastic fibers arranged in flattened laminae which are imperfectly separated by lacunar spaces and blood vessels into two layers: an inner (meningeal) layer and an outer (endosteal) layer, closely connected together, except in certain situations, where they separate to form sinuses for the passages of venous blood or form septae between portions of the brain. The outer surface of the dura mater is rough and fibrillated (composed of fibers), and adheres closely to the inner surfaces of the bones, the adhesions being most marked opposite the cranial sutures (the immovable joints between the bones of the skull or cranium). The endosteal layer is the internal periosteum for the cranial bones, and contains the blood vessels for their supply. The meningeal layer is lined on its inner surface by a layer of unique elongated, flattened fibroblasts that have been called dural border cells. There is no collagen in this layer and the cells are not connected by cell junctions. They are frequently separated by extracellular spaces filled with amorphous nonfilamentous material. The meningeal layer further comprises two lamellas: the compact lamella and the loose lamella; the former generally contains tight fibrous tissue and few blood vessels, but the latter contains some blood vessels.
The processes of the cranial dura mater, which project into the cavity of the skull, are formed by reduplications of the inner (or meningeal) layer of the membrane. These processes include: (1) the falx cerebri, (2) the tentorium cerebelli, (3) the falx cerebelli, and (4) the diaphragma sellae.
The falx cerebri is a strong, arched process with a sickle-like form which descends vertically in the longitudinal fissure between the cerebral hemispheres. It is narrow in front, where it is attached to the ethmoid bone (the bone at the base of the cranium and the root of the nose) at the crista galli (the triangular midline process of the ethmoid bone); and broad behind, where it is connected with the upper surface of the tentorium cerebelli (an arched fold of dura mater that covers the upper surface of the cerebellum). Its upper margin is convex, and attached to the inner surface of the skull in the middle line, as far back as the internal occipital protuberance; it contains the superior sagittal sinus. Its lower margin is free and concave, and contains the inferior sagittal sinus.
The tentorium cerebelli is an arched lamina, elevated in the middle, and inclining downward toward the circumference. It covers the superior surface of the cerebellum, and supports the occipital lobes of the brain. Its anterior border is free and concave, and bounds a large oval opening (the incisura tentorii) for the transmission of the cerebral peduncles (the massive bundle of corticofugal nerve fibers passing longitudinally over the ventral surface of the midbrain on each side of the midline) as well as ascending sensory and autonomic fibers and other fiber tracts. The tentorium cerebelli is attached behind, by its convex border, to the transverse ridges upon the inner surface of the occipital bone, and there encloses the transverse sinuses; and, in front, to the superior angle of the petrous part of the temporal bone on either side, enclosing the superior petrosal sinuses. At the apex of the petrous part of the temporal bone, the free and attached borders meet, and, crossing one another, are continued forward to be fixed to the anterior and posterior clinoid processes respectively. The posterior border of the falx cerebri is attached to the middle line of its upper surface. The straight sinus is placed at the junction of the falx cerebri and the tentorium cerebelli.
The falx cerebelli is a small triangular process of dura mater that separates the two cerebellar hemispheres. Its base is attached, above, to the under and back part of the tentorium; and its posterior margin is attached to the lower division of the vertical crest on the inner surface of the occipital bone. As it descends, it sometimes divides into two smaller folds, which are lost on the sides of the foramen magnum.
The diaphragma sellae is a small circular horizontal fold, which roofs in the sella turcica (a saddlelike prominence on the upper surface of the sphenoid bone of the skull, situated in the middle cranial fossa and dividing it into two halves) and almost completely covers the pituitary gland (hypophysis); a central opening of variable size transmits the infundibulum (a funnel-shaped extension of the hypothalamus connecting the pituitary gland to the base of the brain).
The arteries of the dura mater are numerous. The meningeal branches of the anterior and posterior ethmoidal arteries and of the internal carotid artery, and a branch from the middle meningeal artery supply the dura of the anterior cranial fossa. The middle and accessory meningeal arteries of the internal maxillary artery; a branch from the ascending pharyngeal artery, which enters the skull through the foramen lacerum; branches from the internal carotid artery, and a recurrent branch from the lacrimal artery supply the dura of the middle cranial fossa. Meningeal branches from the occipital artery, one entering the skull through the jugular foramen, and another through the mastoid foramen; the posterior meningeal artery from the vertebral artery; occasional meningeal branches from the ascending pharyngeal artery, entering the skull through the jugular foramen and hypoglossal canal; and a branch from the middle meningeal artery supply the dura of the posterior cranial fossa.
The veins returning the blood from the cranial dura mater anastomose with the diploic veins or end in the various sinuses. Many of the meningeal veins do not open directly into the sinuses, but open indirectly through a series of ampullae, termed venous lacunae. These are found on either side of the superior sagittal sinus, especially near its middle portion, and are often invaginated by arachnoid granulations; they also exist near the transverse and straight sinuses. They communicate with the underlying cerebral veins, and also with the diploic and emissary veins.
The nerves of the cranial dura mater are filaments derived from the trigeminal, glossopharyngeal, vagal, second and third spinal, sphenopalatine, otic, and superior cervical ganglia and supply unmyelinated and myelinated sensory and autonomic fibers.
1.1.2. Arachnoid
The middle meningeal layer, the arachnoid, is a delicate avascular membrane lying between the pia mater and the dura mater. It is separated from the overlying dura mater by the subdural space and from the underlying pia mater by the subarachnoid space, which contains cerebrospinal fluid.
The arachnoid consists of an outer cell layer of low cuboidal mesothelium. There is a space of variable thickness filled with cerebrospinal fluid and traversed by trabeculae and membranes consisting of collagen fibrils and cells resembling fibroblasts. The inner layer and the trabecula are covered by a somewhat low type of cuboidal mesothelium, which in places are flattened to a pavement type and blends on the inner deep layer with the cells of the pia mater. The arachnoid further contains a plexus of nerves derived from the motor root of the trigeminal, the facial, and the accessory cranial nerves.
The cranial part (arachnoidea encephali) of the arachnoid invests the brain loosely, and does not dip into the sulci (depressions or fissures in the surface of the brain) between the gyri (upraised folds or elevations in the surface of the brain), nor into the fissures, with the exception of the longitudinal fissure and several other larger sulci and fissures. On the upper surface of the brain, the arachnoid is thin and transparent; at the base it is thicker. It is slightly opaque toward the central part of the brain, where it extends across between the two temporal lobes in front of the pons so as to leave a considerable space between the pons and the brain.
The arachnoid surrounds the cranial and spinal nerves, and encloses them in loose sheaths as far as their points of exit from the skull.
1.1.3. Subarachnoid Cavity
The subarachnoid cavity or subarachnoid space, which is the space between the outer cellular layer of the arachnoid and the pia mater, is occupied by tissue consisting of trabeculae of delicate connective tissue and intercommunicating channels in which the cerebrospinal fluid is contained. This cavity is small on the surface of the hemispheres of the brain; on the summit of each gyrus, the pia mater and the arachnoid are in close contact, but triangular spaces are left in the sulci between the gyri, in which the subarachnoid trabecular tissue is found, because the pia mater dips into the sulci, whereas the arachnoid bridges across them from gyrus to gyrus. At certain parts of the base of the brain, the arachnoid is separated from the pia mater by wide intervals, which communicate freely with each other and are named subarachnoid cisternae; the subarachnoid tissue in these cisternae is less abundant.
Subarachnoid Cisternae (Cisternae Subarachnoidales)
The cisterna cerebellomedullaris (cisterna magna) is triangular on sagittal section, and results from the arachnoid bridging over the space between the medulla oblongata and the under surfaces of the hemispheres of the cerebellum; it is continuous with the subarachnoid cavity of the spinal cord at the level of the foramen magnum.
The cisterna pontis is a considerable space on the ventral aspect of the pons. It contains the basilar artery, and is continuous caudal to the pons with the subarachnoid cavity of the spinal cord, and with the cisterna cerebellomedullaris; in front of the pons, it is continuous with the cisterna interpeduncularis.
The cisterna interpeduncularis (cisterna basalis) or the basal cistern is a wide cavity where the arachnoid extends across between the two temporal lobes. It encloses the cerebral peduncles and the structures contained in the interpeduncular fossa, and contains part of the arterial circle of Willis. In front, the cisterna interpeduncularis extends forward across the optic chiasma, forming the cisterna chiasmatis, and further on to the upper surface of the corpus callosum. The arachnoid stretches across from one cerebral hemisphere to the other immediately beneath the free border of the falx cerebri, and thus leaves a space in which the anterior cerebral arteries are contained. The cisterna fossae cerebri lateralis is formed in front of either temporal lobe by the arachnoid bridging across the lateral fissure. This cavity contains the middle cerebral artery. The cisterna venae magnae cerebri occupies the interval between the splenium of the corpus callosum and the superior surface of the cerebellum; it extends between the layers of the tela chorioidea of the third ventricle and contains the great cerebral vein.
The subarachnoid cavity communicates with the general ventricular cavity of the brain by three openings; one, the foramen of Majendie, is in the middle line at the inferior part of the roof of the fourth ventricle; the other two (the foramina of Luschka) are at the extremities of the lateral recesses of that ventricle, behind the upper roots of the glossopharyngeal nerves.
The arachnoid villi are tufted prolongations of pia-arachnoid that protrude through the meningeal layer of the dura mater and have a thin limiting membrane. Tufted prolongations of pia-arachnoid composed of numerous arachnoid villi that penetrate dural venous sinuses and effect transfer of cerebrospinal fluid to the venous system are called arachnoid granulations.
An arachnoidal villus represents an invasion of the dura by the arachnoid membrane, whereby arachnoid mesothelial cells come to lie directly beneath the vascular endothelium of the great dural sinuses. Each villus consists of the following parts: (1) in the interior is a core of subarachnoid tissue, continuous with the meshwork of the general subarachnoid tissue through a narrow pedicle, by which the villus is attached to the arachnoid; (2) around this tissue is a layer of arachnoid membrane, limiting and enclosing the subarachnoid tissue; (3) outside this is the thinned wall of the lacuna, which is separated from the arachnoid by a potential space, which corresponds to and is continuous with the potential subdural space; and (4) if the villus projects into the sagittal sinus, it will be covered by the greatly thinned wall of the sinus, which may consist merely of endothelium. Fluid injected into the subarachnoid cavity will find its way into these villi. Such fluid passes from the villi into the venous sinuses into which they project.
1.1.4. Pia Mater
The pia mater is a thin connective tissue membrane that is applied to the surface of the brain and spinal cord. Blood vessels supplying the brain travel through the pia into the brain. The pia mater, which is continuous with the ependyma at the foramen of Majendie and the two foramina of Luschka, is perforated by all the blood vessels as they enter or leave the nervous system, and therefore is considered to be an incomplete membrane. In perivascular spaces, the pia apparently enters as a mesothelial lining of the outer surface of the space; a variable distance from the exterior, these cells become unrecognizable and are apparently lacking, replaced by neuroglia elements. The inner walls of the perivascular spaces likewise seem to be covered for a certain distance by the mesothelial cells, reflected with the vessels from the arachnoid covering of these vascular channels as they traverse the subarachnoid spaces.
The cranial pia mater (pia mater encephali; pia of the brain) invests the entire surface of the brain, dips between the cerebral gyri and cerebellar laminae, and is invaginated to form the tela chorioidea of the third ventricle, and the choroid plexuses of the lateral and third ventricles. As it passes over the roof of the fourth ventricle, it forms the tela chorioidea and the choroid plexuses of the fourth ventricle. On the cerebellum the membrane is more delicate; the vessels from its deep surface are shorter, and its relations to the cortex are not so intimate.
The pia mater forms sheaths for the cranial nerves.
2. Circulation of the Brain
FIGS. 5, 6, 7 and 8 show schematic illustrations of the brain's blood vessels. Each cerebral hemisphere is supplied by an internal carotid artery, which arises from a common carotid artery beneath the angle of the jaw, enters the cranium through the carotid foramen, traverses the cavernous sinus, penetrates the dura (giving off the ophthalmic artery) and divides into the anterior and middle cerebral arteries. The large surface branches of the anterior cerebral artery supply the cortex and white matter of the inferior frontal lobe, the medial surface of the frontal and parietal lobes and the anterior corpus callosum. Smaller penetrating branches supply the deeper cerebrum and diencephalon, including limbic structures, the head of the caudate, and the anterior limb of the internal capsule. The large surface branches of the middle cerebral artery supply most of the cortex and white matter of the hemisphere's convexity, including the frontal, parietal, temporal and occipital lobes, and the insula. Smaller penetrating branches supply the deep white matter and diencephalic structures such as the posterior limb of the internal capsule, the putamen, the outer globus pallidus, and the body of the caudate. After the internal carotid artery emerges from the cavernous sinus, it also gives off the anterior choroidal artery, which supplies the anterior hippocampus and, at a caudal level, the posterior limb of the internal capsule. Each vertebral artery arises from a subclavian artery, enters the cranium through the foramen magnum, and gives off an anterior spinal artery and a posterior inferior cerebellar artery. The vertebral arteries join at the junction of the pons and the medulla to form the basilar artery, which at the level of the pons gives off the anterior inferior cerebellar artery and the internal auditory artery, and, at the midbrain, the superior cerebellar artery. The basilar artery then divides into the two posterior cerebral arteries. The large surface branches of the posterior cerebral arteries supply the inferior temporal and medial occipital lobes and the posterior corpus callosum; the smaller penetrating branches of these arteries supply diencephalic structures, including the thalamus and the subthalamic nuclei, as well as part of the midbrain (see Principles of Neural Sciences, 2d Ed., Eric R. Kandel and James H. Schwartz, Elsevier Science Publishing Co., Inc., New York, pp. 854-56 (1985)).
Interconnections between blood vessels (anastomoses) protect the brain when part of its vascular supply is compromised. At the circle of Willis, the two anterior cerebral arteries are connected by the anterior communicating artery and the posterior cerebral arteries are connected to the internal carotid arteries by the posterior communicating arteries. Other important anastomoses include connections between the ophthalmic artery and branches of the external carotid artery through the orbit, and connections at the brain surface between branches of the middle, anterior, and posterior cerebral arteries (Principles of Neural Sciences, 2d Ed., Eric R. Kandel and James H. Schwartz, Elsevier Science Publishing Co., Inc., New York, pp. 854-56 (1985)).
The circle of Willis at the base of the brain is the principal arterial anastomotic trunk of the brain. Blood reaches it mainly via the vertebral and internal carotid arteries (See FIG. 5); anastomoses occur between arterial branches of the circle of Willis over the cerebral hemispheres and via extracranial arteries that penetrate the skull through various foramina.
The circle of Willis is formed by anastamoses between the internal carotid, basilar, anterior cerebral, anterior communicating, posterior cerebral, and posterior communicating arteries. The internal carotid artery terminates in the anterior cerebral and middle cerebral arteries. Near its termination, the internal carotid artery gives rise to the posterior communicating artery, which joins caudally with the posterior cerebral artery. The anterior cerebral arteries connect via the anterior communicating artery.
2.1. Cerebral Arteries
The blood supply to the cerebral cortex mainly is via cortical branches of the anterior cerebral, middle cerebral, and posterior cerebral arteries, which reach the cortex in the pia mater. FIG. 6 shows an illustrative view of the arterial supply of the cerebral cortex where 1 is the orbitofrontal artery; 2 is the prerolandic artery; 3 is the rolandic artery; 4 is the anterior parietal artery; 5 is the posterior parietal artery; 6 is the angular artery; 7 is the posterior temporal artery; 8 is the anterior temporal artery; 9 is the orbital artery; 10 is the frontopolar artery; 11 is the callosomarginal artery; 12 is the posterior internal frontal artery; and 13 is the pericallosal artery (Correlative Neuroanatomy & Functional Neurology, 18th Ed., p. 50, 1982).
The lateral surface of each cerebral hemisphere is supplied mainly by the middle cerebral artery. The medial and inferior surfaces of the cerebral hemispheres are supplied by the anterior cerebral and posterior cerebral arteries.
The middle cerebral artery, a terminal branch of the internal carotid artery, enters the lateral cerebral fissure and divides into cortical branches that supply the adjacent frontal, temporal, parietal and occipital lobes. Small penetrating arteries, the lenticulostriate arteries, arise from the basal portion of the middle cerebral artery to supply the internal capsule and adjacent structures.
The anterior cerebral artery extends medially from its origin from the internal carotid artery into the longitudinal cerebral fissure to the genu of the corpus callosum, where it turns posteriorly close to the corpus callosum. It gives branches to the medial frontal and parietal lobes and to the adjacent cortex along the medial surface of these lobes.
The posterior cerebral artery arises from the basilar artery at its rostral end usually at the level of the midbrain, curves dorsally around the cerebral peduncle, and sends branches to the medial and inferior surfaces of the temporal lobe and to the medial occipital lobe. Branches include the calcarine artery and perforating branches to the posterior thalamus and subthalamus.
The basilar artery is formed by the junction of the vertebral arteries. It supplies the upper brain stem via short paramedian, short circumferential, and long circumferential branches.
The midbrain is supplied by the basilar, posterior cerebral, and superior cerebellar arteries. The pons is supplied by the basilar, anterior cerebellar, inferior cerebellar, and superior cerebellar arteries. The medulla oblongata is supplied by the vertebral, anterior spinal, posterior spinal, posterior inferior cerebellar, and basilar arteries. The cerebellum is supplied by the cerebellar arteries (superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries).
The choroid plexuses of the third and lateral ventricles are supplied by branches of the internal carotid and posterior cerebral arteries. The choroid plexus of the fourth ventricle is supplied by the posterior inferior cerebellar arteries.
Venous drainage from the brain chiefly is into the dural sinuses, vascular channels lying within the tough structure of the dura. The dural sinuses contain no valves and, for the most part, are triangular in shape. The superior longitudinal sinus is in the falx cerebri.
The human brain constitutes only about 2% of the total weight of the body, but it receives about 15% of cardiac output, and its oxygen consumption is approximately 20% of that for the total body. These values indicate the high metabolic rate and oxygen requirement of the brain that are compensated by a correspondingly high rate of blood flow per unit brain weight. Cerebral circulation is supplied by the internal carotid arteries and the vertebral arteries. The total blood flow to the brain is about 750-1000 ml/min; of this amount about 350 ml flows through each internal carotid artery and about 100-200 ml flows through the vertebral basilar system. The venous outflow is drained by the internal jugular veins and the vertebral veins.
The term “stroke” or “cerebrovascular accident” as used herein refers to the neurological symptoms and signs, usually focal and acute, that result from diseases involving blood vessels. Strokes are either occlusive (due to closure of a blood vessel) or hemorrhagic (due to bleeding from a vessel). The term “ischemia” as used herein refers to a lack of blood supply and oxygen that occurs when reduced perfusion pressure distal to an abnormal narrowing (stenosis) of a blood vessel is not compensated by autoregulatory dilation of the resistance vessels. When ischemia is sufficiently severe and prolonged, neurons and other cellular elements die; this condition is referred to as “infarction.”
Hemorrhage may occur at the brain surface (extraparenchymal), for example from the rupture of congenital aneurysms at the circle of Willis, causing subarachnoid hemorrhage (SAH). Hemorrhage also may be intraparenchymal, for example from rupture of vessels damaged by long-standing hypertension, and may cause a blood clot (intracerebral hematoma) within the cerebral hemispheres, in the brain stem, or in the cerebellum. Hemorrhage may be accompanied by ischemia or infarction. The mass effect of an intracerebral hematoma may compromise the blood supply of adjacent brain tissue; or SAH may cause reactive vasospasm of cerebral surface vessels, leading to further ischemic brain damage. Infarcted tissue may also become secondarily hemorrhagic. Aneurysms occasionally can rupture into the brain, causing an intracerebral hematoma, and into the cerebral ventricles, causing intraventricular hemorrhage.
Although most occlusive strokes are due to atherosclerosis and thrombosis, and most hemorrhagic strokes are associated with hypertension or aneurysms, strokes of either type may occur at any age from many causes, including, without limitation, cardiac disease, trauma, infection, neoplasm, blood dyscrasia, vascular malformation, immunological disorder, and exogenous toxins.
2.2. Vasoconstriction and Vasodilation
The term “vasoconstriction” as used herein refers to the narrowing of blood vessels resulting from contracting of the muscular wall of the vessels. When blood vessels constrict, the flow of blood is restricted or slowed. The term “vasodilation”, which is the opposite of vasoconstriction as used herein, refers to the widening of blood vessels. The terms “vasoconstrictors,” “vasopressors,” or “pressors” as used herein refer to factors causing vasoconstriction. Vasoconstriction usually results in an increase of blood pressure and may be slight or severe. Vasoconstriction may result from disease, medication, or psychological conditions. Medications that cause vasoconstriction include, but are not limited to, catecholamines, antihistamines, decongestants, methylphenidate, cough and cold combinations, pseudoephedrine, and caffeine.
A vasodilator is a drug or chemical that relaxes the smooth muscle in blood vessels causing them to dilate. Dilation of arterial blood vessels (mainly arterioles) leads to a decrease in blood pressure. The relaxation of smooth muscle relies on removing the stimulus for contraction, which depends predominately on intracellular calcium ion concentrations and phosphorylation of myosin light chain (MLC). Thus, vasodilation predominantly works either 1) by lowering intracellular calcium concentration, or 2) by dephosphorylation of MLC, which includes the stimulation of myosin light chain phosphatase and the induction of calcium symporters and antiporters (which pump calcium ions out of the intracellular compartment). The re-uptake of ions into the sarcoplasmic reticulum of smooth muscle via exchangers and expulsion of ions across the plasma membrane also helps to accomplish vasodilation. The specific mechanisms to accomplish these effects vary from vasodilator to vasodilator and may be grouped as endogenous and exogenous. The term “endogenous” as used herein refers to proceeding from within or derived internally; or resulting from conditions within the organism rather than externally caused. The term “exogenous” as used herein refers to originating from outside; derived externally; or externally caused rather than resulting from conditions within the organism.
Vasodilation directly affects the relationship between mean arterial pressure and cardiac output and total peripheral resistance (TPR). Cardiac output may be computed by multiplying the heart rate (in beats/minute) and the stroke volume (the volume of blood ejected during systole). TPR depends on several factors, including, but not limited to, the length of the vessel, the viscosity of blood (determined by hematocrit), and the diameter of the blood vessel. Blood vessel diameter is the most important variable in determining resistance. An increase in either cardiac output or TPR cause a rise in the mean arterial pressure. Vasodilators work to decrease TPR and blood pressure through relaxation of smooth muscle cells in the tunica media layer of large arteries and smaller arterioles.
Vasodilation occurs in superficial blood vessels of warm-blooded animals when their ambient environment is hot; this process diverts the flow of heated blood to the skin of the animal, where heat may be more easily released into the atmosphere. Vasoconstriction is the opposite physiological process. Vasodilation and vasoconstriction are modulated naturally by local paracrine agents produced by endothelial cells (e.g., bradykinin, adenosine, nitric oxide, endothelins), as well as by an organism's autonomic nervous system and adrenal glands, both of which secrete catecholamines, such as norepinephrine and epinephrine, respectively.
Vasodilators are used to treat conditions such as hypertension, where the patient has an abnormally high blood pressure, as well as angina and congestive heart failure, where maintaining a lower blood pressure reduces the patient's risk of developing other cardiac problems.
Cerebral Ventricles
Cerebral ventricles, which are chambers in the brain that contain cerebrospinal fluid, include two lateral ventricles, one third ventricle, and one fourth ventricle. The lateral ventricles are in the cerebral hemispheres. They drain via the foramen of Monroe into the third ventricle, which is located between the two diencephalic structures of the brain. The third ventricle leads, by way of the aqueduct of Sylvius, to the fourth ventricle. The fourth ventricle is in the posterior fossa between the brainstem and the cerebellum. The cerebrospinal fluid drains out of the fourth ventricle through the foramenae of Luschka and Magendie to the basal cisterns. The cerebrospinal fluid then percolates through subarachnoid cisterns and drains out via arachnoid villi into the venous system.
FIG. 9 is a diagram of the ventricular system of the brain. The system is a series of cavities (ventricles) within the brain and is continuous with both the subarachnoid space and central canal of the spinal cord. There are four cerebral ventricles: the right and left lateral ventricles, and the midline third and fourth ventricles. The two lateral ventricles are located within the cerebrum and each connects to the third ventricle through an interventricular foramen of Monroe. The third ventricle is located in the diencephalon and is connected to the fourth ventricle by the cerebral aqueduct of Sylvius. The fourth ventricle is located in the hind brain and it is continuous with the central canal of the spinal cord, at least embryologically. Three foramina connect the fourth ventricle to the subarachnoid space: the median aperture or foramen of Magendie, and left and right lateral apertures (foramena) of Luschka.
2.4. CSF Flow in the Brain
FIG. 10 shows an illustrative view of CSF flow from the ventricles to the subarachnoid space. Cerebrospinal fluid (CSF) is a clear bodily fluid that occupies the ventricular system, subarachnoid space of the brain, and central canal of the spinal cord. CSF is produced by modified ependymal cells of the choroid plexus found throughout the ventricular system; it is also formed around blood vessels and ventricular walls, presumably from the extracellular space of the brain. CSF flows from the lateral ventricles via interventricular foramina into the third ventricle. CSF then flows into the fourth ventricle through the cerebral aqueduct. CSF flows out in the subarachnoid space via the median aperture and left and right lateral apertures. Finally, the CSF is reabsorbed into the dural venous sinuses through arachnoid granulations and arachnoid villi. Arachnoid granulations consist of collections of villi. The villi are visible herniations of the arachnoid membrane through the dura and into the lumen of the superior sagittal sinus and other venous structures. The granulations appear to function as valves that allow one-way flow of CSF from the subarachnoid spaces into venous blood. All constituents of CSF leave with the fluid, including small molecules, proteins, microorganisms, and red blood cells.
CSF is produced at a rate of approximately 0.3-0.37 ml/minute or 20 ml/hour or 500 ml/day. The volume of the CSF space is about 150 mL and the CSF turns over 3.7 times a day.
The choroid plexus uses capillary filtration and epithelial secretory mechanisms to maintain the chemical stability of the CSF. While the capillaries that traverse the choroid plexus are freely permeable to plasma solutes, a barrier exists at the level of the epithelial cells that make up the choroid plexus, which is responsible for carrier-mediated active transport. CSF and extracellular fluids of the brain are in a steady state and blood plasma and CSF are in osmotic equilibrium under normal physiological conditions.
2.5. Blood Brain Barrier
The blood brain barrier (BBB) prevents entry of blood-borne substances into the brain and maintains a stable environment for neurons to function effectively. It results from specialized properties of brain microvessel endothelial cells, the principal anatomic site of the BBB, their intercellular junctions, and a relative lack of vesicular transport, which makes such cells different from those of general capillaries. Endothelial cells of blood-brain barrier vessels also are not fenestrated; instead they are interconnected by complex arrays of tight junctions, which block diffusion across the vessel wall.
3. Subarachnoid Hemorrhage
The term “subarachnoid hemorrhage” (also referred to as “SAH”) refers to bleeding into the subarachnoid space. SAH may occur spontaneously, usually from a cerebral aneurysm, or may result from trauma. A cerebral aneurysm is a weakness in the wall of an artery of the brain that results in circumscribed dilation of the artery, such that the wall(s) of the blood vessel expand outward. Cerebral aneurysms tend to be located in the circle of Willis and its branches. Where SAH is caused by a rupture of an intracranial aneurysm, i.e., aneurysmal SAH (“aSAH”), bleeding is seen in the subarachnoid space, and less commonly in the intraventricular and intracerebral spaces. Bleeding due to SAH may result in brain damage, brain shift, decreased cerebral perfusion and hydrocephalus. Symptoms include an intense headache with a rapid onset (sometimes referred to as a “thunderclap headache”), vomiting, and an altered level of consciousness. Diagnosis generally is made with computed tomography (CT scanning), or occasionally by lumbar puncture. FIG. 11A shows a flow diagram for prognosis following SAH and FIG. 11B shows a flow diagram of pathways proposed to be involved in delayed complications after SAH.
SAH is a medical emergency and may lead to death or severe disability even if recognized and treated at an early stage. About 35% of all SAH cases are fatal, with 10-15% of patients dying before arriving at a hospital. SAH is considered a form of stroke, and causes between 1% and 7% of all strokes. Aneurysmal SAH constitutes on an average about 85% of all cases of spontaneous SAH. While most cases of SAH are due to bleeding from small aneurysms, larger aneurysms (which are rarer) are more likely to rupture. No aneurysm is detected from the first angiogram in 15% of cases of spontaneous SAH. Non-aneurysmal perimesencephalic hemorrhage, in which the blood is limited to the area of the prepontine, interpeduncular and adjacent subarachnoid cisterns, causes 67% of the SAH cases in which no aneurysm is detected. The remaining 33% of cases are due to vasculitic damage to arteries, other disorders affecting the vessels, disorders of the spinal cord blood vessels, bleeding into various tumors, and a number of other causes. Most traumatic SAHs occur near a skull fracture or intracerebral contusion.
In the United States, it is estimated that the incidence of SAH from a ruptured intracranial aneurysm is 1 case per 10,000 persons, yielding approximately 34,000 new cases of SAH each year. These ruptured aneurysms have a 30-day mortality rate of about 35%. About 15% of patients die before reaching hospital and an additional 20% or so die within 30 days of the hemorrhage. (Nieuwkamp D J et al., “Changes in case fatality of aneurysmal subarachnoid hemorrhage over time, according to age, sex, and region: a meta-analysis,” Lancet Neurol., 8:635-642 (2009)). An estimated 30% of survivors will have moderate-to-severe disability. The morbidity is substantial in those who survive, with 75% suffering permanent neurological or neurocognitive impairment. (Al-Khindi T. et al., “Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage,” Stroke, 41:e519-e536, (2010)). Thus, only about 20% of all patients survive and resume their previous lifestyle by 3 to 6 months after aneurysmal SAH. The burden of aneurysmal SAH is disproportionately high compared to ischemic stroke because of the high likelihood of permanent disability and the relative youth of those affected (51 years of age for aSAH compared to 75-years old for ischemic stroke). (Taylor, T. N. et al., “Lifetime cost of stroke in the United States,” Stroke, 27:1459-1466 (1996)). FIG. 12 shows time trends in outcome of SAH in seven population-based studies of SAH, which shows 50% decrease in mortality over 20 years.
A systematic review of the incidence of SAH revealed that the overall incidence of SAH is on average 9.1 per 100,000 annually. Studies from Japan and Finland show higher rates in those countries (22.7 per 100,000 and 19.7 per 100,000, respectively), for reasons that are not entirely understood. South and Central America, in contrast, have a rate of 4.2 per 100,000 on average. The group of people at risk for SAH is younger than the population usually affected by stroke, but the risk still increases with age. Young people are much less likely than middle-aged people (risk ratio 0.1, or 10%) to suffer a SAH. The risk continues to rise with age and is 60% higher in the very elderly (over 85) than in those between 45 and 55. Risk of SAH is about 25% higher in women above 55, possibly reflecting the hormonal changes that result from the menopause (de Rooij, N. K. et al., “Incidence of subarachnoid hemorrhage: a systematic review with emphasis on region, age, gender and time trends,” Journal of Neurology, Neurosurgery, and Psychiatry, 2007, 78(12): 1365-1372; Feigin, V. L. et al., “Risk factors for subarachnoid hemorrhage an updated systematic review of epidemiological studies,” Stroke, 2005, 36(12): 2773-2780).
Symptoms of SAH
The classic symptom of SAH is thunderclap headache (a headache described as the “worst ever” or an “explosion in the head,” developing over seconds to minutes) although it is a symptom in only about a third of all SAH patients. Approximately 10% of patients who seek medical care with this symptom have an underlying SAH. Patients also may present with vomiting, and 1 in 14 have seizures. Neck stiffness and other signs of meningism may be present, as may confusion, decreased level of consciousness, or coma. Intraocular hemorrhage may occur in response to the raised pressure inside the head (intracranial pressure). Subhyaloid (the hyaloid membrane envelopes the vitreous body of the eye) and vitreous hemorrhage may be visible on fundoscopy. This is known as Terson syndrome (occurring in 3-13% of cases), and is more common in more severe SAH. In a patient with thunderclap headache, none of the aforementioned signs are helpful in confirming or ruling out hemorrhage, although seizures are more common if the bleeding is the result of a ruptured aneurysm as opposed to other causes. Oculomotor nerve abnormalities (affected eye movement downward and outward, inability to lift the eyelid on the same side but normal pupillary reflexes) may indicate bleeding from an aneurysm arising near the posterior communicating artery. Isolated dilation of a pupil may also reflect brain herniation as a result of increased intracranial pressure.
The body releases large amounts of adrenaline and similar hormones as a result of the bleeding, which leads to a sudden increase in the blood pressure. The heart comes under substantial strain, and neurogenic pulmonary edema, stunned myocardium, cardiac arrhythmias, electrocardiographic changes (with occasional giant inverted “cerebral” T waves), tsako tsubo cardiomyopathy and cardiac arrest (3%) may rapidly occur after the onset of hemorrhage.
SAH also may occur in people who have suffered a head injury. Symptoms may include headache, decreased level of consciousness or hemiparesis. SAH is regarded as a severe complication of head injury, especially if it is associated with lower Glasgow Coma Scale levels.
Diagnosis of SAH
The initial steps for evaluating a person with a suspected SAH are the steps of obtaining a medical history and performing a physical examination. Since only 10-25% of patients admitted to a hospital with a thunderclap headache are suffering from a SAH, other possible causes usually are considered simultaneously, such as meningitis, migraine, and cerebral venous sinus thrombosis. Intracerebral hemorrhage, which is twice as common as SAH, occasionally is misdiagnosed as SAH.
A diagnosis of SAH cannot be made on clinical grounds alone. Generally, medical imaging [usually computed tomography (CT) scan, which has a high sensitivity (>95% correct identification especially on the first day after the onset of bleeding)] of the brain is required to confirm or exclude bleeding. Magnetic resonance imaging (MRI) may be more sensitive after several days when compared to CT scan. In people with normal CT or MRI scans, lumbar puncture, in which cerebrospinal fluid (CSF) is removed with a needle from the lumbar sac, shows evidence of hemorrhage in 3% of the group in whom the CT was found to be normal; lumbar puncture is therefore regarded as mandatory if imaging is negative. The CSF sample is examined for xanthochromia, the yellow appearance of centrifuged fluid, or by using spectrophotometry for bilirubin, a breakdown product of hemoglobin in the CSF.
After an SAH is confirmed, its origin needs to be determined. CT angiography (“CTA”) (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms is generally the first step, although the more invasive catheter angiography (injecting radiocontrast through a catheter advanced to the brain arteries) is the gold standard test but has a higher risk of complications. The latter is useful if there are plans to obliterate the source of bleeding, such as an aneurysm, at the same time.
Classification of SAH
Several grading scales available for SAH have been derived by retrospectively matching characteristics of patients with their outcomes.
The Glasgow Coma Scale (GCS) has been used ubiquitously in the clinical assessment of post-traumatic unconsciousness; it assesses 15 points covering three components: eye (E), verbal (V) and motor (M) response to external stimuli. (Teasdale G. et al., “Assessment of coma and impaired consciousness,” Lancet, 2(7872): 81084 (1974); Teasdale, G. et al., “Assessment and prognosis of coma after head injury,” Acta Neurochir., 34: 45-55 (1976)). Table 1 shows the categorization of the Glasgow Coma Scale.
TABLE 1Categorization of Glasgow Coma ScaleCOMPONENTSPOINTS OF ASSESSMENTE—Eye OpeningC. Not assessable4. Spontaneous3. To speech2. To pain1. NoneV—VerbalT. Not assessableResponse5. Oriented conversation4. Confused speech3. Inappropriate words2. Incomprehensible sounds1. NoneM—Motor6. Obeys simple commandsResponse5. Localizes pain4. Withdraws (normal flexion)3. Stereotyped flexion2. Stereotyped extension1. None
The Glasgow Outcome Scale (GOS) and its extended form (eGOS) are global scales measuring functional outcome of patient status. The five categories of the Glasgow outcome scale were extended to eight categories in the extended Glasgow Outcome Scale. (Jennett, B. and Bond, M., “Assessment of outcome after severe brain damage,” Lancet, 1: 480-484 (1975); Teasdale, G. M. et al., “Analyzing outcome of treatment of severe head injury: A review and update on advancing the use of the Glasgow Outcome Scale,” Journal of Neurotrauma, 15: 587-597 (1998); Wilson, J. T. L. et al., “Structured interviews for the Glasgow Outcome Scale and the Extended Glasgow Outcome Scale,” Journal of Neurotrauma, 15(8): 573-585 (1997); Wilson, J. T. et al., “Observer variation in the assessment of outcome in traumatic brain injury: experience from a multicenter, international randomized clinical trial,” Neurosurgery, 61(1): 123-128 (2007)). Tables 2 and 3 show the categorization scheme used in the Glasgow Outcome Scale (GOS) and in the extended Glasgow Outcome Scale (eGOS), respectively.
TABLE 2Categorization of the Glasgow Outcome ScaleSCORECATEGORYSYMBOL1DEADD2VEGETATIVE STATEVSUnable to interact with environment;unresponsive3SEVERE DISABILTYSD−Able to follow commands/unable to liveindependently4MODERATE DISABILITYMDAble to live independently; unable toreturn to work or school5GOOD RECOVERYGRAble to return to school
TABLE 3Categorization of the Extended Glasgow Outcome ScaleSCORECATEGORYSYMBOL1DeathD2Vegetative StateVS3Lower severe disabilitySD−4Uppoer severe disabilitySD+5Lower moderate disabilityMD−6Upper moderate disabilityMD+7Lower good recoveryGR−8Upper good recoveryGR+
A scale of severity was described by Hunt and Hess in 1968 (“Hunt and Hess scale”) and categorizes the clinical condition of the patient. The Fisher Grade classifies the appearance of SAH on CT scan. The Fisher scale has been modified by Claassen and coworkers (“Claassen scale”), reflecting the additive risk from SAH size and accompanying intraventricular hemorrhage. The World Federation of Neurological Surgeons classification uses GCS and focal neurological deficit to gauge severity of symptoms. A comprehensive classification scheme has been suggested by Ogilvy and Carter to predict outcome and gauge therapy. The Ogilvy system has five grades, assigning one point for the presence or absence of each of five factors: (1) age greater than 50; (2) Hunt and Hess grade 4 or 5; (3) Fischer scale 3 or 4; (4) aneurysm size greater than 10 mm; and (5) posterior circulation aneurysm 25 mm or more.
The Barthel index, frequently used in stroke evaluation, is an objective functional scale that measures a patient's independence in activities of daily living (ADL), including feeding, bathing, grooming, dressing, bowel and bladder control, wheelchair management and ascending and descending stairs. (Granger C. V. et al., “Measurement of outcome of care for stroke patients,” Stroke, 6:34-41 (1975)). The Montreal Cognitive Assessment (MoCA) test is a screening tool for mild cognitive dysfunction. (Nasreddine Z. S. et al., “The Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impairment,” J. Am. Geriatr. Soc., 53: 695-699 (2005)). The modified Rankin scale is a 7-point scale (0 is the best and 6 is the worst score) that assesses patient condition based on their or their care-givers' response to simple questions about their daily functioning (van Swieten, J. C. et al., “Interobserver agreement for the assessment of handicap in stroke patients,” Stroke 19:604-607 (1988)). The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurological examination stroke scale that is used to evaluate the severity of neurological deficit after a stroke, such as an ischemic stroke or DCI. It assesses level of consciousness, language, neglect, visual field loss, extraocular movement, motor strength, ataxia, dysarthria and sensory loss.
Prognosis of SAH
Early Morbidity and Mortality
The mortality rate for SAH is between 30% and 40%. Of those who survive initial hospitalization, treatment and complications, at least 25% have significant restrictions in their lifestyle, and less than 20% have no residual symptoms whatsoever. Delay in diagnosis of minor SAH without coma (or mistaking the sudden headache for migraine or some other less serious illness) contributes to poor outcome. Risk factors for poor outcome include higher age, poorer neurological grade, more blood and larger aneurysm on the initial CT scan, location of an aneurysm in the posterior circulation, systolic hypertension, and a previous diagnosis of heart attack, hypertension, liver disease or a previous SAH. During the hospital stay, occurrence of delayed ischemia resulting from vasospasm, development of intracerebral hematoma or intraventricular hemorrhage (bleeding into the ventricles of the brain), and presence of fever on the eighth day of admission also worsen the prognosis.
Angiographic vasospasm was suggested to cause death after aneurysmal SAH in up to 35% of patients in the 1970s and in less than 10% currently. However, outcome overall is still poor, and current rescue therapies, such as hemodynamic therapy, endovascular balloon or pharmacological angioplasty, are associated with substantial morbidity, and are expensive and labor intensive. (Clyde B L et al., “The relationship of blood velocity as measured by transcranial doppler ultrasonography to cerebral blood flow as determined by stable xenon computed tomographic studies after aneurysmal subarachnoid hemorrhage,” Neurosurgery, 38:896-904 (1996)). Among patients with aneurysmal SAH, the incremental cost for symptomatic vasospasm, which is roughly the same as DCI, was $39,971 in the United States in 2010. (Chou C H et al., “Costs of vasospasm in patients with aneurysmal subarachnoid hemorrhage,” Neurosurgery, 67:345-352 (2010)).
SAH that does not show an aneurysm by complete catheter angiography may be referred to as “angiogram-negative SAH.” This carries a better prognosis than SAH from an aneurysm; however, it still is associated with a risk of ischemia, rebleeding and hydrocephalus. Perimesencephalic SAH (bleeding around the mesencephalon part of the brain) is a subgroup of angiogram-negative SAH. It has a very low rate of rebleeding or delayed ischemia, and the prognosis of this subtype is better.
Long-Term Outcomes
Symptoms, such as fatigue, mood disturbances, depression, executive dysfunction and related neurocognitive symptoms, are common in people who have suffered SAH. Even in those who have made a good neurological recovery, anxiety, depression, posttraumatic stress disorder and cognitive impairment are common. Over 60% report frequent headaches. Aneurysmal SAH may lead to damage of the hypothalamus and the pituitary gland, two areas of the brain that play a central role in hormonal regulation and production. Studies indicate that at least 25% of people with a previous SAH may develop deficiencies in one or more of the hypothalamic-pituitary hormones, such as growth hormone, prolactin or thyroid-stimulating hormone.
4. Secondary Complications of SAH
Patients who survive SAH also are at risk of secondary complications. Among these complications are, most notably, aneurysmal re-bleeding, angiographic cerebral vasospasm and delayed cerebral ischemia (DCI). (Macdonald R L et al., “Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials,” Neurocrit. Care, 13:416-424 (2010); Macdonald R L et al., “Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage,” J. Neurosurg. 99:644-652 (2003)).
4.1. Delayed Cerebral Ischemia (DCI)
Delayed cerebral ischemia occurs in 30% of patients with aSAH and causes death or permanent disability in half of these patients. (Dorsch N W C, and King M T, “A review of cerebral vasospasm in aneurysmal subarachnoid hemorrhage. Part 1: Incidence and effects,” Journal of Clinical Neuroscience, 1:19-26 (1994)). The risk of DCI is not easily predicted; the most important factor is the volume of SAH seen on admission cranial computed tomography (CT). (Harrod C G et al., “Prediction of cerebral vasospasm in patients presenting with aneurysmal subarachnoid hemorrhage: a review,” Neurosurgery, 56:633-654 (2005); Reilly C et al., “Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage,” J. Neurosurg. 101:255-261 (2004)).
DCI is a delayed neurological deterioration due to ischemia, associated with the occurrence of focal neurological impairment (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect), and/or a decrease in the Glasgow coma scale (either the total score or one of its individual components [eye, motor on either side, verbal]). (Frontera J A et al., “Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition?” Stroke, 40:1963-1968 (2009); Kassell N F et al., “The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results,” J. Neurosurg., 73:18-36 (1990); Vergouwen M D et al., “Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update,” Stroke, 41:e47-e52 (2010)). This may or may not last for at least one hour, is not apparent immediately after aneurysm occlusion and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies. DCI and development of delayed cerebral infarction are among the most important causes of poor outcome after SAH.
Cerebral infarction may be a consequence of DCI; infarction due to DCI is defined as the presence of an area of brain cell death resulting from insufficiency of arterial or venous blood supply to the brain. It is detected by CT or MRI scan of the brain within 6 weeks after SAH, or on the latest CT or MRI scan made before death within 6 weeks, or proven at autopsy, not present on the CT or MRI scan between 24 and 48 hours after early aneurysm occlusion, and not attributable to other causes such as surgical clipping or endovascular treatment. Hypodensities on CT imaging resulting from ventricular catheter or intraparenchymal hematoma generally are not regarded as evidence of cerebral infarction from DCI.
Angiographic vasospasm is one process that contributes to DCI. Other processes that may contribute to DCI are cortical spreading ischemia and formation of microthromboemboli. Cortical spreading ischemia, which was described in animal models of SAH as a novel mechanism that may cause DCI, has been detected in humans with SAH and angiographic vasospasm.
4.2. Vasospasm
DCI is usually associated with angiographic cerebral vasospasm. The term “angiographic cerebral vasospasm” refers to the narrowing of the large capacitance arteries at the base of the brain (i.e., cerebral arteries) following hemorrhage into the subarachnoid space, leads to reduced perfusion of distal brain regions, and can be detected by either CT angiography [CTA], MR angiography [MRA] or catheter angiography [CA]). It is the most common cause of focal ischemia after SAH; it adversely affects outcome in patients with SAH as it accounts for up to 23% of SAH-related disability and death. Of all types of ischemic stroke, angiographic vasospasm is unique in that it is, to some degree, preventable and treatable (see Macdonald, R. L. and Weir. B. In Cerebral Vasospasm. Academic Press, Burlington, Mass., USA (2001)).
Generally, angiographic vasospasm of the cerebral arteries begins 3 days after SAH, is maximal 7 to 8 days later and resolves by 14 days. (Weir B. et al., “Time course of vasospasm in man,” J. Neurosurg., 48:173-178 (1978)). About 67% of patients with SAH develop vasospasm, 33% develop DCI and 15% of SAH patients die or sustain permanent disability from DCI.
While angiographic vasospasm is a consequence of SAH, it also can occur after any condition that deposits blood in the subarachnoid space. Vasospasm results in decreased cerebral blood flow and increased cerebral vascular resistance. Without being limited by theory, it generally is believed that vasospasm is caused by local injury to vessels, such as that which results from atherosclerosis and other structural injury including traumatic head injury, aneurysmal subarachnoid hemorrhage and other causes of SAH. Cerebral vasospasm is a naturally occurring vasoconstriction that also may be triggered by the presence of blood in the CSF, a common occurrence after rupture of an aneurysm or following traumatic head injury. Cerebral vasospasm ultimately can lead to brain cell damage, in the form of cerebral ischemia and infarction, due to interrupted blood supply. Potential manifestation of symptoms from vasospasm occurs only in those patients who survive past the first few days.
The incidence of vasospasm is less than the incidence of SAH (since only some patients with SAH develop vasospasm). The incidence of vasospasm will depend on the type of patient a given hospital receives and the methods by which vasospasm is diagnosed.
The unqualified term “vasospasm” is usually used with reference to angiographically determined arterial narrowing as defined above. “Clinical vasospasm” most often is used synonymously with delayed cerebral ischemia (DCI). When used in another fashion, for instance, vasospasm based on increased middle cerebral artery transcranial Doppler velocities, this should be specified (Vergouwen, M. D. et al., “Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group,” Stroke 41:2391-2395 (2010)).
Some degree of angiographic narrowing will occur in at least two-thirds of patients having angiography between 4 and 12 days after SAH. The numbers of patients developing neurological deterioration from angiographic vasospasm varies with the diligence with which the patient is monitored and the efficacy of prophylaxis, but it has been estimated at about one-third. Of hospitalized SAH patients, about 5% die from vasospasm. When compared to post-SAH patients of intermediate grade, post-SAH patients in very good condition are less likely to develop vasospasm as they have small volume SAH, while post-SAH patients in very poor condition are more likely to die earlier from the initial episode. The presence of thick, widespread subarachnoid clot which can be visualized on the computerized tomographic (CT) scan done in close proximity to the bleeding episode is a key prognostic factor. The chance of vasospasm and consequently DCI is decreased by factors decreasing the duration of exposure to clot. Conversely, the incidence of vasospasm and DCI is increased by the utilization of antifibrinolytic drugs which prolong the exposure of arteries to clot and possibly cause ischemia by other mechanisms. Poor admission clinical grade is associated with DCI, presumably because they both indicate larger volumes of SAH. A definite relationship between age, hypertension, or sex and DCI has not been established. It is possible that smokers are more prone to vasospasm and DCI. Factors unrelated to the development of vasospasm include season, geography, contrast material, and diabetes.
Patients who develop vasospasm do worse than those who do not. If neurosurgical clipping or endovascular coiling of the ruptured aneurysm is performed earlier (within the first day or so) the outcome tends to be better than if treatment is delayed. When operations were preferentially performed during the peak period for vasospasm, outcomes were generally worse. Vasospasm does not result from early surgery or coiling; early surgery or coiling permits more vigorous treatment should vasospasm develop. If a thick clot is present, an attempt at careful removal of the clot is sometimes made. The amount of residual clot postoperatively is a prognostic factor for DCI. Open operation exposes the patient to retractor pressure, venous sacrifice, temporary clipping ischemia, and arterial injury. Studies have shown post operative decrease in cerebral blood flow, regional cerebral metabolic rate of oxygen, and oxygen extraction ratio. Vasospasm and DCI may be more common in patients who undergo neurosurgical clipping of a ruptured aneurysm as compared to endovascular coiling.
Independent variables, such as admission neurologic grade, increasing age, and massive intracranial or intraventricular hemorrhage, are more closely linked to outcome than vasospasm. Since vasospasm is a graded process, it is expected that only the extreme cases will result in infarction in the absence of systemic hypotension, cardiac dysfunction, anoxia, and intracranial hypertension. Preexisting hypertension and advanced age also strongly influence the vulnerability of the brain to ischemia. The etiological relationship between vasospasm and infarction in fatal cases is not in dispute.
There is evidence that vasospasm may be reduced by clot removal either surgically or pharmacologically. There also are data suggesting that DCI may be lessened by pharmacologically induced hypertension and hypervolemia as well as by calcium antagonists. Vasospasm also may be abolished by mechanical or transiently by pharmacologic angioplasty.
Incidence of Vasospasm
The incidence of angiographic vasospasm depends on the time interval after the SAH. The peak incidence occurs 6-8 days after SAH (range, 3-12 days). In addition to the time after the SAH, other principal factors that affect the prevalence of vasospasm are the volume, density, temporal persistance and distribution of subarachnoid blood.
Prognostic Factors for Vasospasm
Prognostic factors for angiographic vasospasm include: the amount of subarachnoid blood on CT scan; hypertension; anatomical and systemic factors; clinical grade; and whether the patient is receiving antifibrinolytics.
Diagnosis of Vasospasm
The diagnosis of angiographic vasospasm rests on comparison of blood vessel imaging studies. The diagnosis of delayed cerebral ischemia (DCI) is primarily clinical. Angiographic vasospasm can be asymptomatic; however, when the cerebral blood flow is below ischemic threshold, symptoms become apparent, and this is called DCI. Symptoms typically develop subacutely and may fluctuate. Symptoms may include excess sleepiness, lethargy, stupor, hemiparesis or hemiplegia, abulia, language disturbances, visual fields deficits, gaze impairment, and cranial nerve palsies. Although some symptoms are localized, they are not diagnostic of any specific pathological process; therefore alternative diagnoses, such as rebleeding, hydrocephalus, and seizures, should be excluded promptly using radiographic, clinical and laboratory assessments. Cerebral angiography is the gold standard for visualizing and studying cerebral arteries; transcranial Doppler ultrasonography is also utilized.
The pathophysiology of angiographic vasospasm may involve structural changes and biochemical alterations within the vascular endothelium and smooth muscle cells. The presence of blood in the subarachnoid space initiates these changes. In addition, hypovolemia and an impaired cerebral autoregulatory function may concurrently interfere with cerebral perfusion and contribute to DCI due to angiographic vasospasm. The cumulative effects of these processes can lead to reduction in cerebral blood flow so severe as to cause cerebral ischemia leading to infarction. Additionally, a period of severe constriction could lead to morphologic changes in the walls of the cerebral arteries, which may cause them to remain narrowed without the continued presence of vasoactive substances. The area of the brain supplied by the affected artery then would experience ischemia (meaning a restriction in blood supply).
Other Complications
Hydrocephalus (a condition marked by an excessive accumulation of CSF resulting in dilation of the cerebral ventricles and raised intracranial pressure) may complicate SAH in both the short- and long-term, and may be detected on CT scanning. If the level of consciousness is decreased, surgical drainage of the excess fluid (for instance with a ventricular drain or shunt) is occasionally necessary.
Fluctuations in blood pressure and electrolyte disturbances, as well as pneumonia and cardiac decompensation, occur in about 50% of hospitalized patients with SAH, and may worsen prognosis. They are managed symptomatically.
Seizures occur in about a tenth of all cases of SAH.
5. Voltage-Gated Ion Channels
Voltage-gated ion channels are a class of integral membrane proteins that allow the passage of selected inorganic ions across the cell membrane by opening and closing in response to changes in transmembrane voltage. (Sands, Z. et al., “Voltage-gated ion channels,” Current Biology, 15(2): R44-R47 (2005)). These types of ion channels are especially critical in neurons, but are common in many types of cells. They have an important role in excitable neuronal and muscle tissues as they allow a rapid and coordinated depolarization in response to triggering voltage change. Positioned along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals.
Structure
Voltage-gated potassium, sodium and calcium ion channels are thought to have similar overall architectures. (Sands, Z. et al., “Voltage-gated ion channels,” Current Biology, 15(2): R44-R47 (2005)). Voltage-gated ion channels generally are composed of severα1 subunits arranged such that there is a central pore through which ions can travel down their electrochemical gradients. The channels tend to be quite ion-specific, although similarly sized and charged ions may also travel through them to some extent.
Mechanism
Crystallographic structural studies of a potassium channel, assuming that this structure remains intact in the corresponding plasma membrane, suggest that when a potential difference is introduced over the membrane, the associated electromagnetic field induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the channel, or cavity, opens to admit ion influx or efflux to occur across the membrane, down its electrochemical gradient. This subsequently generates an electrical current sufficient to depolarize the cell membrane.
Voltage-gated sodium channels and calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. The voltage sensing helix, S4, has multiple positive charges such that a high positive charge outside the cell repels the helix and induces a conformational change such that ions may flow through the channel. Potassium channels function in a similar way, with the exception that they are composed of four separate polypeptide chains, each comprising one domain. The voltage-sensitive protein domain of these channels (the “voltage sensor”) generally contains a region composed of S3b and S4 helices, known as the “paddle” due to its shape, which appears to be a conserved sequence.
5.1. Voltage-Dependent Calcium Channels
Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels that control calcium entry into cells in response to membrane potential changes. (Van Petegem F. et al., Biochemical Society Transactions, 34(5): 887-893 (2006)). Voltage-dependent calcium channels are found in excitable cells (e.g., muscle, glial cells, neurons, etc.). At physiologic or resting membrane potential, VDCCs are normally closed. They are activated (i.e., opened) at depolarized membrane potentials. Activation of particular VDCCs allows Ca2+ entry into the cell; muscular contraction, excitation of neurons, upregulation of gene expression, or release of hormones or neurotransmitters results, depending upon the cell type. (Catterall W. A. et al., “International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels,” Pharmacol. Rev., 57(4): 411-25 (2005); Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002)).
Voltage-dependent calcium channels are formed as a complex of several different subunits: α1, α2δ, β1-4, and γ. The α subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating. (Dolphin A. C. “A short history of voltage-gated calcium channels,” Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))
α1 Subunit
The α1 subunit pore (about 190 kDa in molecular mass) is the primary subunit necessary for channel functioning in the VDCC, and consists of the characteristic four homologous I-IV domains containing six transmembrane α-helices each. The α subunit forms the Ca2+ selective pore, which contains voltage-sensing machinery and the drug/toxin-binding sites. Ten α subunits that have been identified in humans. (Dolphin A. C. “A short history of voltage-gated calcium channels,” Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006)).
a2δ Subunit
The α2δ gene encodes two subunits, α2 and δ. They are linked to each other via a disulfide bond and have a combined molecular weight of 170 kDa. The α2 is the extracellular glycosylated subunit that interacts the most with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion, which serves to anchor the protein in the plasma membrane. There are 4 α2δ genes: CACNA2D1 (CACNA2D1), (CACNA2D2), (CACNA2D3), and (CACNA2D4). Co-expression of the α2δ enhances the level of expression of the α1 subunit and causes an increase in current amplitude, faster activation and inactivation kinetics and a hyperpolarizing shift in the voltage dependence of inactivation. Some of these effects are observed in the absence of the betα subunit, whereas, in other cases, the co-expression of beta is required. The α2δ-1 and α2δ-2 subunits are binding sites for at least two anticonvulsant drugs, gabapentin and pregabalin, that also find use in treating chronic neuropathic pain. (Dolphin A. C. “A short history of voltage-gated calcium channels,” Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))
β Subunit
The intracellular β subunit (55 kDa) is an intracellular membrane-associated guanylate kinase (MAGUK)-like protein containing a guanylate kinase (GK) domain and an SH3 (src homology 3) domain. The guanylate kinase domain of the β subunit binds to the alpha subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the β subunit: CACNB1, CACNB2, CACNB3, and CACNB4. (Dolphin A. C. “A short history of voltage-gated calcium channels,” Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))
Without being limited by theory, it is postulated the cytosolic β subunit has a major role in stabilizing the final α subunit conformation and delivering it to the cell membrane by its ability to mask an endoplasmic reticulum retention signal in the α subunit. The endoplasmic retention brake is contained in the I-II loop of the α subunit that becomes masked when the β subunit binds. Therefore the β subunit functions initially to regulate the current density by controlling the amount of α subunit expressed at the cell membrane.
In addition to this potential trafficking role, the β subunit has the added important functions of regulating activation and inactivation kinetics, and hyperpolarizing the voltage-dependence for activation of the α subunit pore, so that more current passes for smaller depolarizations. The β subunit acts as an important modulator of channel electrophysiological properties. The interaction between a highly conserved 18-amino acid region on the α1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain, AIDBP) and a region on the GK domain of the β subunit (Alpha Interaction Domain Binding Pocket) is responsible for the regulatory effects exerted by the β subunit. Additionally, the SH3 domain of the β subunit also gives added regulatory effects on channel function, indicating that the β subunit may have multiple regulatory interactions with the α1 subunit pore. The α interaction domain sequence does not appear to contain an endoplasmic reticulum retention signal; this may be located in other regions of the I-II α1 subunit linker.
γ Subunit
The γ1 subunit is known to be associated with skeletal muscle VDCC complexes, but the evidence is inconclusive regarding other subtypes of calcium channel. The γ1 subunit glycoprotein (33 kDa) is composed of four transmembrane spanning helices. The γ1 subunit does not affect trafficking, and, for the most part, is not required to regulate the channel complex. However, γ2, γ3, γ4 and γ8 also are associated with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, non-NMDA-type ionotropic transmembrane receptors for glutamate that mediate fast synaptic transmissions in the CNS. An NMDA-type receptor is a receptor to which NMDA (N-methyl-D-aspartate) binds specifically. There are 8 genes for gamma subunits: γ1 (CACNG1), γ2 (CACNG2), γ3 (CACNG3), γ4 (CACNG4), (CACNG5), (CACNG6), (CACNG7), and (CACNG8). (Chu P. J. et al., “Calcium channel gamma subunits provide insights into the evolution of this gene family,” Gene, 280 (1-2): 37-48 (2002)).
Voltage dependent calcium channels vary greatly in structure and form. Calcium channels are classified as L-, N-, P/Q, T- and R-type according to their pharmacological and electrophysiological properties. These channel subtypes have distinct physiological functions. Molecular cloning has clarified the α1 subunit sequence of each channel. The α1 subunit has a specific role in eliciting activity in an individual channel. Nonetheless, selective antagonists for these channel subtypes are required for defining specific channels involved in each activity. The neural N-type channels are blocked by ω-conotoxin GVIA; the R-type channels are resistant to other antagonists and toxins, are blocked by SNX-482, and may be involved in processes in the brain; the closely related P/Q-type channels are blocked by co-agatoxins. The dihydropyridine-sensitive L-type channels are responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle and for hormone secretion in endocrine cells and also are antagonized by phenylalkylamines and benzothiazepines.
5.2. Types of Voltage-Dependent Calcium Channels
L-Type Calcium Channels
L-type voltage-gated calcium channels are opened when a smooth muscle cell is depolarized. This depolarization may be brought about by stretching of the cell, by an agonist-binding its G protein-coupled receptor (GPCR), or by autonomic nervous system stimulation. Opening of the L-type calcium channel causes influx of extracellular Ca2+, which then binds calmodulin. The activated calmodulin molecule activates myosin light-chain kinase (MLCK), which phosphorylates the myosin in thick filaments. Phosphorylated myosin is able to form cross bridges with actin thin filaments, and the smooth muscle fiber (i.e., cell) contracts via the sliding filament mechanism. (Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002))
L-type calcium channels also are enriched in the t-tubules of striated muscle cells, such as, skeletal and cardiac myofibers. As in smooth muscle, L-type calcium channels open when these cells are depolarized. In skeletal muscle, since the L-type calcium channel and the calcium-release channel (ryanodine receptor, or RYR) are mechanically gated to each other with the latter located in the sarcoplasmic reticulum (SR), the opening of the L-type calcium channel causes the opening of the RYR. In cardiac muscle, opening of the L-type calcium channel permits influx of calcium into the cell. The calcium binds to the calcium release channels (RYRs) in the SR, opening them (referred to as “calcium-induced calcium release” or “CICR”). Ca2+ is released from the SR and is able to bind to troponin C on the actin filaments regardless of how the RYRs are opened, either through mechanical-gating or CICR. The muscles then contract through the sliding filament mechanism, causing shortening of sarcomeres and muscle contraction.
R-Type Voltage Dependent Calcium Channels
R-type voltage dependent calcium channels (VDCC) are involved in regulating calcium flow. The R-type VDCCs play an important role in decreased cerebral blood flow observed following SAH. Without being limited by theory, R-type voltage-dependent Ca2+ channels that may be located within small diameter cerebral arteries may regulate global and local cerebral blood flow, since the concentration of intracellular free calcium ions determines the contractile state of vascular smooth muscle. (Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002)).
R-type voltage dependent calcium channel inhibitors are calcium entry blocking drugs whose main pharmacological effect is to prevent or slow the entry of calcium into cells via R-type voltage-gated calcium channels. The gene Cav2.3 encodes the principal pore-forming unit of R-type voltage-dependent calcium channels being expressed in neurons.
N-Type Calcium Channels
N-type (‘N’ for “Neural-Type”) calcium channels are found primarily at presynaptic terminals and are involved in neurotransmitter release. Strong depolarization by an action potential causes these channels to open and allow influx of Ca2+, initiating vesicle fusion and release of stored neurotransmitter. N-type channels are blocked by ω-conotoxin. (Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002)).
P/Q-Type Calcium Channels
P-type (‘P’ for cerebellar Purkinje cells) calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal, and in neuronal integration in many neuronal types. They also are found in Purkinje fibers in the electrical conduction system of the heart (Winds, R., et al., J. Physiol. (Lond.) 305: 171-95 (1980); Llinds, R. et al., Proc. Natl. Acad. Sci. U.S.A. 86 (5): 1689-93 (1989)). Q-type calcium channel antagonists appear to be present in cerebellar granule cells. They have a high threshold of activation and relatively slow kinetics. (Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002)).
T-Type Calcium Channels
T-type (‘T’ for transient) calcium channel antagonists are low voltage-activated. They most often are found in neurons and cells that have pacemaker activity and in osteocytes. Mibefradil shows some selectivity for T-type over other types of VDCC. (Yamakage M. et al, “Calcium channels—basic aspects of their structure, function and gene encoding; anesthetic action on the channels—a review,” Can. J. Anaesth., 49(2): 151-64 (2002)).
5.3. Antagonists and Inhibitors of Calcium Channels
Calcium channel antagonists are a class of drugs and natural substances having effects on many excitable cells of the body, such as the muscle of the heart, smooth muscles of the vessels or neuron cells. The primary action of many calcium channel antagonists is to decrease blood pressure, via L-type calcium channel blockade. (Survase, S. et al., “Actions of calcium channel blockers on vascular proteoglycan synthesis: relationship to atherosclerosis,” Vasc. Health Risk Manag., 1(3): 199-208 (2005)).
Calcium channel antagonists act upon voltage-dependent calcium channels (VDCCs) in muscle cells of the heart and blood vessels. By blocking the calcium channel they prevent large increases of the calcium levels in the cells when stimulated, which subsequently leads to less muscle contraction. In the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in blood vessel diameter. The resultant vasodilation decreases total peripheral resistance, while a decrease in cardiac contractility decreases cardiac output. Since blood pressure is in part determined by cardiac output and peripheral resistance, blood pressure drops.
Calcium channel antagonists do not decrease the responsiveness of the heart to input from the sympathetic nervous system. Since blood pressure regulation is carried out by the sympathetic nervous system (via the baroreceptor reflex), calcium channel antagonists allow blood pressure to be maintained more effectively than do β-blockers. However, because calcium channel antagonists result in a decrease in blood pressure, the baroreceptor reflex often initiates a reflexive increase in sympathetic activity leading to increased heart rate and contractility. The decrease in blood pressure also likely reflects a direct effect of antagonism of VDCC in vascular smooth muscle, leading to vasodilation. A β-blocker may be combined with a calcium channel antagonist to minimize these effects.
Calcium channel antagonists may decrease the force of myocardial contraction, an effect that depends on the chemical class of antagonist. This is known as the “negative inotropic effect” of calcium channel antagonists. (Bryant, B. et al., “Pharmacology for health professionals,” 3rd Ed., Elsevier Australia (2010)). Most calcium channel antagonists are not the preferred choice of treatment in individuals with cardiomyopathy due to their negative inotropic effects. (Lehne, R., “Pharmacology for nursing care,” 7th Ed., St. Louis, Mo., Saunders Elsevier., p. 505 (2010)).
Some calcium channel antagonists exhibit a negative dromotropic effect in that they slow the conduction of electrical activity within the heart by blocking the calcium channel during the plateau phase of the action potential of the heart. This effect is known as a “negative dromotropic effect”. Some calcium channel antagonists can also cause a lowering of the heart rate and may cause heart block (which is known as the “negative chronotropic effect” of calcium channel antagonists). The negative chronotropic effects of calcium channel antagonists make them a commonly used class of agents for control of the heart rate in individuals with atrial fibrillation or flutter. (See for example, Murphy C. E. et al., “Calcium channel blockers and cardiac surgery,” J. Card. Surg., 2(2): 299-325 (1987)).
The antagonists for L, N, and P/Q-types of calcium channels are utilized in distinguishing channel subtypes. For the R-type calcium channel subtype, for example, ω-agatoxin IIIA shows blocking activity, even though its selectivity is rather low. This peptide binds to all of the high voltage-activated channels including L, N, and P/Q subtypes (J. Biol. Chem., 275, 21309 (2000)). A putative R-type (or class α1E) selective blocker, SNX-482, a toxin from the tarantula Hysterocrates gigas, is a 41 amino acid residue peptide with 3 disulfide linkages (1-4, 2-5 and 3-6 arrangement) (Biochemistry, 37, 15353 (1998), Peptides 1998, 748 (1999)). This peptide blocks the class E calcium channel (IC50=15 nM to 30 nM) and R-type calcium current in the neurohypophysial nerve endings at 40 nM concentration. R-type (class E) calcium channel blocking activity is highly selective; no effect is observed on K+ and Na+ currents, and L, P/Q and T-type calcium currents. N-type calcium current is blocked only weakly 30-50% at 300 nM to 500 nM. Regionally, different sensitivity of R-type current to SNX-482 is observed; no significant effect on R-type current occurs in preparations of the neuronal cell body, retinal ganglion cells and hippocampal pyramidal cells. Using SNX-482, three a E-calcium subunits with distinct pharmacological properties are recognized in cerebellar R-type calcium channels (J. Neurosci., 20, 171 (2000)). Similarly, it has been shown that secretion of oxytocin, but not vasopressin, is regulated by R-type calcium current in neurohypophysial terminals (J. Neurosci., 19, 9235 (1999)).
Dihydropyridine calcium channel antagonists often are used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina (with the exception of amlodipine, which carries an indication to treat chronic stable angina as well as vasospastic angina) since the vasodilation and hypotension can lead to reflex tachycardia. This calcium channel antagonist class is easily identified by the suffix “-dipine.”
Phenylalkylamine calcium channel antagonists are relatively selective for myocardium. They reduce myocardial oxygen demand and reverse coronary vasospasm. They have minimal vasodilatory effects compared with dihydropyridines. Their action is intracellular.
Benzothiazepine calcium channel antagonists are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. Benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines due to their cardiac depressant and vasodilator actions.
L-type VDCC inhibitors are calcium entry blocking drugs whose main pharmacological effect is to prevent or slow entry of calcium into cells via L-type voltage-gated calcium channels. Examples of such L-type calcium channel inhibitors include, but are not limited to: dihydropyridine L-type antagonists such as nisoldipine, AHF (such as 4aR,9aS)-(+)-4-a-Amino-1,2,3,4,4a,9a-hexahydro-4a14-fluorene, HCl), isradipine (such as 4-(4-Benzofurazanyl)-1,-4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calciseptine (such as isolated from (Dendroaspis polylepis ploylepis), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn-Thr-Cys-Tyr-Lys-Met- Phe-Ile-Arg-Thr-Gln-Arg- Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met-Trp-Pro-Tyr-Gl-n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH [SEQ ID NO: 1], Calcicludine (such as isolated from Dendroaspis angusticeps (eastern green mamba)), (H-Trp -Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys-Lys-Gln-Phe-Ser-Ser -Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly-Gly-Asn -Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH [SEQ ID NO: 2], Cilnidipine (such as also FRP-8653, a dihydropyridine-type inhibitor), Dilantizem (such as (2S,3S)-(+)-cis-3-Acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride), diltiazem (such as benzothiazepine-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-(+)-cis-monohydrochloride), Felodipine (such as 4-(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylic acid ethyl methyl ester), FS-2 (such as an isolate from Dendroaspis polylepis polylepisvenom), FTX-3.3 (such as an isolate from Agelenopsis aperta), Neomycin sulfate (such as C23H46N6O13.3H2SO4), Nicardipine (such as 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenylmethyl-2-[methyl(phenylmethylamino]-3,5-pyridinedicarboxylic acid ethyl ester hydrochloride, also YC-93, Nifedipine (such as 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester), Nimodipine (such as 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (Isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate), Nitrendipine (such as 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester), S-Petasin (such as (3S,4aR,5R,6R)-[2,3,4,4a,5,6,7,8-Octahydro-3-(2-propenyl)-4-a,5-dimethyl-2-o-xo-6-naphthyl]Z-3′-methylthio-1′-propenoate), Phloretin (such as 2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)propiophenone, also 3-(4-Hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-1-propanone, also b-(4-Hydroxyphenyl)-2,4,6-trihydroxypropiophenone), Protopine (such as C20H19NO5Cl), SKF-96365 (such as 1-[b-[3-(4-Methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole, HCl), Tetrandine (such as 6,6′,7,12-Tetramethoxy-2,2′-dimethylberbaman), (+/−)-Methoxyverapamil or (+)-Verapamil (such as 54N-(3,4-Dimethoxyphenylethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-iso-propylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (such as R-(+)-1,4-Dihydro-2,6-dimethyl-5-nitro-442-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester). The foregoing examples may be specific to L-type voltage-gated calcium channels or may inhibit a broader range of voltage-gated calcium channels, e.g. N, P/Q, R, and T-type.
6. Endothelins
Endothelins are small vasoconstricting peptides (21 amino acids) produced in vivo primarily in the endothelium that increase blood pressure and vascular tone, and play an important role in vascular homeostasis. This family of peptides includes endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3). ET-1 is secreted mostly by vascular endothelial cells. The predominant ET-1 isoform is expressed in vasculature and is the most potent vasoconstrictor. ET-1 also has inotropic, chemotactic and mitogenic properties. It stimulates the sympathetic nervous system, and influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide. Endothelins are among the strongest vasoconstrictors known and have been implicated in vascular diseases of several organ systems, including the heart, general circulation and brain.
There are two key endothelin receptor types, ETA and ETB. ETA and ETB have distinct pharmacological characteristics. The ETA-receptor affinity is much higher for ET-1 than for ET-3. ETA-receptors are located in the vascular smooth muscle cells, but not in endothelial cells. The binding of endothelin to ETA increases vasoconstriction and the retention of sodium, leading to increased blood pressure. ETB receptors primarily are located on the endothelial cells that line the interior of the blood vessels. There may be ETB receptors on smooth muscle cells which mediate contraction. Endothelin binding to ETB receptors lowers blood pressure by increasing natriuresis and diuresis, and releasing nitric oxide. ET-1 and ET-3 activate the ETB-receptor equally, which in turn leads to vasodilation via production of NO and prostaglandins. Endothelin-1 (ET-1) also has been demonstrated to cause vascular smooth muscle constriction via ETA-receptor stimulation and to induce nitric oxide (NO) production in endothelial cells via ETB-receptors. Some ETB-receptors are located in vascular smooth muscle, where they may mediate vasoconstriction. A number of endothelin receptors are regulated by various factors. Angiotensin II and phorbol esters down-regulate endothelin receptors whereas ischemia and cyclosporin increase the number of endothelin receptors. (Reviewed in Aapitov, A. V. et al., “Role of endothelin in cardiovascular disease,” Journal of Renin-Angiotensin-Aldosterone System, 3(1): 1-15 (2002)).
A number of peptide and nonpeptide ET antagonists have been studied. ETA-receptor antagonists may include, but are not limited to, A-127722 (non-peptide), ABT-627 (non-peptide), BMS 182874 (non-peptide), BQ-123 (peptide), BQ-153 (peptide), BQ-162 (peptide), BQ-485 (peptide), BQ-518 (peptide), BQ-610 (peptide), EMD-122946 (non-peptide), FR 139317 (peptide), IPI-725 (peptide), L-744453 (non-peptide), LU 127043 (non-peptide), LU 135252 (non-peptide), PABSA (non-peptide), PD 147953 (peptide), PD 151242 (peptide), PD 155080 (non-peptide), PD 156707 (non-peptide), RO 611790 (non-peptide), SB-247083 (non-peptide), clazosentan (non-peptide), atrasentan (non-peptide), sitaxsentan sodium (non-peptide), TA-02 01 (non-peptide), TBC 11251 (non-peptide), TTA-386 (peptide), WS-7338B (peptide), ZD-1611 (non-peptide), and aspirin (non-peptide). ETA/B-receptor antagonists may include, but are not limited to, A-182086 (non-peptide), CGS 27830 (non-peptide), CP 170687 (non-peptide), J-104132 (non-peptide), L-751281 (non-peptide), L-754142 (non-peptide), LU 224332 (non-peptide), LU 302872 (non-peptide), PD 142893 (peptide), PD 145065 (peptide), PD 160672 (non-peptide), RO-470203 (bosentan, non-peptide), RO 462005 (non-peptide), RO 470203 (non-peptide), SB 209670 (non-peptide), SB 217242 (non-peptide), and TAK-044 (peptide). ETB-receptor antagonists may include, but are not limited to, A-192621 (non-peptide), A-308165 (non-peptide), BQ-788 (peptide), BQ-017 (peptide), IRL 1038 (peptide), IRL 2500 (peptide), PD-161721 (non-peptide), RES 701-1 (peptide), and RO 468443 (peptide). (Aapitov, A. V. et al., “Role of endothelin in cardiovascular disease,” Journal of Renin-Angiotensin-Aldosterone System, 3(1): 1-15 (2002)).
ET-1 is translated initially to a 212 amino-acid peptide (pre-proendothelin-1). It is further converted to proendothelin-1 after removal of the secretory sequence. Proendothelin-1 then is cleaved by furin to generate the biologically-inactive precursor big endothelin-1. Mature ET-1 is formed upon cleavage of big endothelin-1 by one of several endothelin-converting enzymes (ECEs). There are two splice variants of ECE-1; these are ECE-1a and ECE-1b. Each has functionally distinct roles and tissue distribution. ECE-1a is expressed in the Golgi network of endothelin-producing cells and cleaves big endothelin-1 to form ET-1. ECE-1b is localized at the plasma membrane and cleaves extracellular big endothelin-1. Both ECE-1a and ECE-1b are inhibited by metalloprotease inhibitor phosphoramidon. ECEs also are located on α-actin filaments in smooth muscle cells. ECE inhibition by phosphoramidon completely blocks vasoconstriction to big endothelin-1. ECE inhibitors may include, but are not limited to, B-90063 (non-peptide), CGS 26393 (non-peptide), CGS 26303 (non-peptide), CGS 35066 (non peptide), phosphoramidon (peptide), PP-36 (peptide), SM-19712 (non-peptide), and TMC-66 (non-peptide). (Aapitov, A. V. et al., “Role of endothelin in cardiovascular disease,” Journal of Renin-Angiotensin-Aldosterone System, 3(1): 1-15 (2002)).
In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin and other vasoconstrictors on the one hand and nitric oxide, prostacyclin and other vasodilators on the other. Endothelin antagonists may have a role in the treatment of cardiac, vascular and renal diseases associated with regional or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure, chronic renal failure, and SAH.
7. Transient Receptor Potential Channels
The transient receptor potential (TRP) channel family is a member of the calcium channel group. These channels include transient receptor potential protein and homologues thereof, the vanilloid receptor subtype I, stretch-inhibitable non-selective cation channel, olfactory, mechanosensitive channel, insulin-like growth factor I-regulated calcium channel, and vitamin D-responsive apical, epithelial calcium channel (ECaC). (see for example, Montell C. et al., “Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction, Neuron, 2(4):1313-1323 (1989); Caterina et al., “The capsaicin receptor: a heat-activated ion channel in the pain pathway,” Nature, 389 (6653): 816-824 (1997); Suzuki et al., “Cloning of a stretch-inhibitable nonselective cation channel,” J. Biol. Chem. 274: 6330-6335 (1999); Kiselyov et al., “Functional interaction between InsP3 receptors and store-operated Htrp3 channels,” Nature 396 (6710): 478-482 (1998); Hoenderop et al., “Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia,” J. Biol. Chem. 274(13): 8375-8378 (1999); and Chen et al., “Polycystin-L is a calcium-regulated cation channel permeable to calcium ions,” Nature, 401(6751): 383-386 (1999)). Each of these molecules is at least 700 amino acids in length, and shares certain conserved structural features. Predominant among these structural features are six transmembrane domains, with an additional hydrophobic loop present between the fifth and sixth transmembrane domains. It is believed that this loop is integral to the activity of the pore of the channel formed upon membrane insertion. TRP channel proteins also include one or more ankyrin domains and frequently display a proline-rich region at the N-terminus.
Based on amino acid homology, the TRP superfamily can be further subdivided into sub-families. In mammals, these include TRPC (canonical), TRPV (vanilloid), TRPM (melastanin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. The TRPC (canonical) subfamily includes 7 TRP channels (TRPC1-7); the TRPM (melastanin) subfamily includes eight different channels (TRPM1-8); the TRPV (vanilloid) subfamily includes six members (TRPV1-6); the TRPA (ankyrin) subfamily includes one member (TRPA1) and the TRPP (polycystin) and TRPML (mucolipin) subfamilies each include three mammalian members. In addition, the TRPN (No mechanopotential) found in hearing assisting sensory neurons have been identified in Drosophila and zebrafish. (Nilius, B. et al., “Transient receptor potential cation channels in disease,” Physiol. Rev. 87: 165-217 (2007)).
Transient receptor potential (TRP) cation channels are present in vascular smooth muscle and are involved in the smooth muscle depolarizing response to stimuli such as membrane stretch. Uridine triphosphate (UTP) invokes membrane depolarization and constriction of vascular smooth muscle by activating a cation current that exhibits inward rectification, is not rapidly desensitized, and is blocked by gadolinium ions (Gd3+). Canonical transient receptor potential (TRPC) proteins form Ca2+ permeable, non-selective cation channels in a variety of mammalian tissues. Suppression of one member of this family of channels, TRPC6, has been reported to prevent an alpha-adenoreceptor-activated cation current in cultured rabbit portal vein myocytes. However, suppression of TRPC6 channels in cerebral vascular smooth muscle does not attenuate the UTP-induced membrane depolarization and vasoconstriction. In contrast, TRPC3, unlike TRPC6, has been found to mediate the agonist induced depolarization, as observed in rat cerebral artery, following UTP activation of the P2Y receptor. Thus, TRPC3 channels in vascular smooth muscle mediate agonist-induced depolarization which contributes to vasoconstriction in resistance-sized cerebral arteries.
The TRP1 channel family comprises a large group of channels mediating an array of signal and sensory transduction pathways. The proteins of the mammalian TRPC subfamily are the products of at least seven genes coding for cation channels that appear to be activated in response to phospholipase C(PLC)-coupled receptors. The putative ion channel subunits TRPC3, TRPC6, and TRPC7 comprise a structurally related subgroup of the family of mammalian TRPC channels. The ion channels formed by these proteins appear to be activated downstream of phospholipase C (PLC). PLC-dependent activation of TRPC6 and TRPC7 has been shown to involve diacylglycerol and is independent of G proteins or inositol 1,4,5-triphosphate (IP3).
TRPC channels are widely expressed among cell types and may play important roles in receptor-mediated Ca2+ signaling. The TRPC3 channel is known to be a Ca2+-conducting channel activated in response to PLC-coupled receptors. TRPC3 channels have been shown to interact directly with intracellular inositol 1,4,5-trisphosphate receptors (InsP3Rs), i.e., channel activation is mediated through coupling to InsP3Rs.
Agents useful for increasing arterial blood flow, inhibiting vasoconstriction or inducing vasodilation are agents that inhibit TRP channels. These inhibitors embrace compounds that are TRP channel antagonists. Such inhibitors are referred to as activity inhibitors or TRP channel activity inhibitors. As used herein, the term “activity inhibitor” refers to an agent that interferes with or prevents the activity of a TRP channel. An activity inhibitor may interfere with the ability of the TRP channel to bind an agonist such as UTP. An activity inhibitor may be an agent that competes with a naturally occurring activator of TRP channel for interaction with the activation binding site on the TRP channel. Alternatively, an activity inhibitor may bind to the TRP channel at a site distinct from the activation binding site, but in doing so, it may, for example, cause a conformational change in the TRP channel, which is transduced to the activation binding site, thereby precluding binding of the natural activator. Alternatively, an activity inhibitor may interfere with a component upstream or downstream of the TRP channel but which interferes with the activity of the TRP channel. This latter type of activity inhibitor is referred to as a functional antagonist. Non-limiting examples of a TRP channel inhibitor that is an activity inhibitor are gadolinium chloride, lanthanum chloride, SKF 96365 and LOE-908.
8. Regression Analyses for Selection of Eligible Subjects
DCI and cerebral infarction are associated with poor outcome. A systematic review and meta analysis of twenty one randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, including 7788 patients, and had both cerebral infarction and clinical outcome as outcome events were performed. (Asano T et al., “Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial,” J. Neurosurg., 84:792-803 (1996); Chou S H et al., “A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage,” Stroke, 39:2891-2893 (2008); Fisher C M et al., “Cerebral vasospasm with ruptured saccular aneurysm—the clinical manifestations,” Neurosurgery, 1:245-248 (1977); Gomis P et al., “Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage,” J. Neurosurg., 112:681-688 (2010); Haley E C, Jr. et al., “A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America,” J. Neurosurg., 86:467-474 (1997); Haley E C, Jr. et al., “A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study,” J. Neurosurg., 78:537-547 (1993); Hop J W et al., “Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage,” Neurology, 54:872-878 (2000); Kassell N F et al., “Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand,” J. Neurosurg., 84:221-228 (1996); Lanzino G, and Kassell N F, “Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America,” J. Neurosurg., 90:1018-1024 (1999); Lanzino G et al., “Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa,” J. Neurosurg., 90:1011-1017 (1999); Macdonald R L et al., “Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial,” Stroke, 39:3015-3021 (2008); Ohman J, and Heiskanen O, “Effect of nimodipine on the outcome of patients after aneurysmal subarachnoid hemorrhage and surgery,” J. Neurosurg. 69:683-686 (1988); Pickard J D et al., “Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial,” BMJ, 298:636-642 (1989); Saito I et al., “Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage,” Neurosurgery, 42:269-277 (1998); Shaw M D, et al. “Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the p,”Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Grou J. Neurosurg., 93:992-997 (2000); Springborg J B et al., “Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial,” Acta Neurochir. (Wien)) 149:1089-1101 (2007); Tseng M Y, et al., “Interaction of Neuroprotective and Hematopoietic Effects of Acute Erythropoietin Therapy with Age, Sepsis, and Statins Following Aneurysmal Subarachnoid Hemorrhage,” Presented at the XIV World Congress of Neurological Surgery of the World Federation of Neurosurgical Societies, Boston, Mass., August 30-Sep. 4, 2009 (Abstract); van den Bergh W M et al., “Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study,” Stroke 37:2326-2330 (2006); Westermaier T et al., “Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, clinical study,” Crit. Care Med. 38:1284-1290 (2010); Etminan, N. et al., “Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis,” J. Cereb. Blood Flow Metab. 31:1443-1451 (2011)).
Effect sizes were expressed in (pooled) risk ratio estimates with corresponding 95% confidence intervals (CI). Sensitivity analyses were performed for studies with a low risk of bias, and for those who reported outcome at three months after SAH. The risk of bias is assessed for “allocation concealment” and “blinding” (Day, S. et al., “Blinding in clinical trials,” BMJ, 321: 504 (2000)). To avoid selection bias, it is a tenet of randomized controlled trials that the treatment allocation for each patient is not revealed until the patient has irrevocably been entered into the trial. This sort of blinding is referred to as “allocation concealment.” In controlled trials the term “blinding,” and in particular “double blind,” usually refers to keeping study participants, those involved with their management and those collecting and analyzing clinical data unaware of the assigned treatment so that they are not influenced by that knowledge.
Pharmaceutical treatments decreased the incidence of both cerebral infarction (Relative Risk (“RR”) 0.83; 95% CI ranging from 0.74-0.94) and of poor functional outcome (Relative Risk (“RR”) 0.91; 95% CI ranging from 0.85-0.98). (Vergouwen, M. D. et al., “Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage,” J. Cereb. Blood Flow Metab., 31:1545-1553 (2011)). Thus, there is an association between infarction, a principle component of the diagnosis of DCI, and outcome. Since the mechanism of action of most of the drugs used is to either reverse angiographic vasospasm or protect the brain, these data suggest that the association between cerebral infarction and functional outcome implies causality.
Logistic regression analysis was performed with randomized clinical trial data with 3,567 patients between 1991 and 1997 to assess the relationships and interactions between admission neurological grade assessed on the WFNS, subarachnoid clot thickness, DCI and clinical outcome. (Haley E C, Jr. et al., “A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America,” J. Neurosurg., 86:467-474, (1997); Kassell N F et al., “Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand,” J. Neurosurg., 84:221-228 (1996); Lanzino G, and Kassell N F, “Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America,” J. Neurosurg., 90:1018-1024 (1999)).
Clinical outcome was the dependent variable and was assessed 3 months after SAH on the Glasgow Outcome Scale (GOS). (Jennett B, and Bond M, “Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480-484, 1975). Independent variables assessed included World Federation of Neurosurgical Surgeons (WFNS) grade, age and subarachnoid clot thickness, factors found to be associated with outcome. (Rosengart A J, et al. “Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage,” Stroke 38:2315-2321 (2007)). The other variables present on admission that were of similar importance were intraventricular hemorrhage, intracerebral hemorrhage and history of hypertension. The multivariable logistic regression theoretically selects variables independently associated with poor outcome. Thus, both subarachnoid clot volume and WFNS grade are important. If DCI is the dependent variable, then the variables significantly associated with are age, again showing an inverted U-shaped relationship with a peak incidence among patients 40 to 59-years-old. (Macdonald R L et al., “Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage,” J. Neurosurg. 99:644-652 (2003)). Other significant variables were history of hypertension, WFNS grade, subarachnoid clot thickness, aneurysm size and intraventricular hemorrhage. Thus, both neurological grade and subarachnoid clot thickness predict subsequent development of DCI.
The Co-operative Study on Timing of Aneurysm Surgery collected data from 68 centers across Europe, North America, Australia, Japan and South Africa. (Kassell N F et al., “The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results,” J. Neurosurg., 73:18-36 (1990)). 3521 patients were enrolled within 3 days of an SAH. At admission 75% of patients had a good neurological grade, defined as having normal speech at admission. Logistic regression analysis showed that that the extent of SAH as assessed by clot thickness on the admission CT scan, is an independent risk factor for development of DCI and infarction. The study found that patients who had a normal CT scan had a low risk of developing DCI, and the risk increased progressively with increasing amounts of blood on CT, with patients having thick focal blood being at the highest risk. The study also showed that development of DCI could not be predicted by the presence of focal motor signs, cranial nerve palsies, language defects, impaired responsiveness, nuchal rigidity or severity of headache at admission. Based on the results of this study, the predictive power of CT for DCI exceeds that of clinical neurological examination.
Hijdra, et al., reported on 176 patients admitted within 72 hours of SAH, who were prospectively studied to assess the predictive value of clinical and radiological features for DCI, rebleeding and outcome. (Hijdra A et al., “Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage,” Stroke 19:1250-1256 (1988)). At baseline, 49% of patients were Hunt and Hess grades 1-2, and 51% were Hunt and Hess 3-5. Hunt and Hess grades 1-2 would be roughly equivalent to WFNS grade 1 and Hunt and Hess 3-5 to WFNS grades 2-5.24% of the patients with admission Hunt and Hess grades 1-2 developed DCI and 51% of them died or were vegetative or had severe disability (poor or unfavorable GOS) at 3 months. Stepwise logistic regression analysis showed that death, vegetative state or severe disability was best predicted by the amount of subarachnoid blood on CT scan within 72 hours of rupture (p=0.0001) and admission Glasgow coma score (GCS, p=0.0030). Blood on CT was a stronger predictor than GCS. The analysis also showed that amount of SAH on CT was the most important predictor of DCI, followed by amount of intraventricular hemorrhage, and that the predictive power of these two factors could not be improved further by taking into account the patient's initial neurological condition.
Öhman, et al., prospectively studied 265 good grade patients with aneurysmal SAH to examine which radiological and clinical factors forecast the development of cerebral infarct as a consequence of DCI. (Öhman J et al., “Risk factors for cerebral infarction in good-grade patients after aneurysmal subarachnoid hemorrhage and surgery: a prospective study,” J. Neurosurg. 74:14-20 (1991)). Of these, 104 patients were randomized to receive nimodipine, 109 placebo and 52 received no treatment. The 161 patients who received either placebo or no treatment were analyzed together. At admission 31% of patients were Hunt and Hess grade 1, 44% were grade 2, and 25% were grade 3. Baseline CT showed that 21% of patient had no or small amount of blood on CT, 18% had thin layers of blood, 42% had thick layers of blood and 18% had severe bleeding. Patients were followed up at 1-3 years post-hemorrhage at which time CT scans were performed and evaluated for presence or absence of infarction and GOS was assessed at the same time. Logistic regression analysis showed that, in order of importance, the following factor were strongly predictive of infarction: severe bleeding on admission CT, history of hypertension and thick layers of blood in the basal cisterns on admission CT. Post-operative angiograms were done on 213 patients. 78 patients had moderate or severe vasospasm and 65% of them had infarction on follow up CT scans. Clinical grade at admission had no significant effect on cerebral infarction. There was an apparent trend for grade 3 patients to have more infarcts but the differences between neurological grades did not reach significance.
Woertgen and colleagues studied 292 patients with aneurysmal SAH (“aSAH”) between 1995 and 2000 with the aim of comparing clinical scales and CT findings to predict DCI. (Woertgen C et al., “Comparison of the Claassen and Fisher C T classification scale to predict ischemia after aneurysmatic SAH?” Zentralbl Neurochir 64:104-108 (2003)). DCI was defined as new cerebral infarction on CT. Correlations between admission Hunt and Hess grade, Fisher grade 39 and Claassen grades 23 with cerebral infarction on CT were analyzed. The outcome at 3 months, based on the GOS, was also analyzed, with unfavorable outcome defined as death, vegetative or severe disability and favorable outcome defined as moderate disability or good recovery. The odds ratio (meaning the ratio of the odds of developing an infarct in one grade to the odds of developing an infarct in the control group) for infarction was calculated at each level of the grading scales. The control group was the grade with the lowest risk of infarction, that is, Hunt and Hess grade 0. In terms of the impact of infarction on outcome at 3 months, 63% of patients (183/292) had favorable outcome and 37% had unfavorable outcome. Of those that had favorable outcome, only 9% had an infarct on CT, whereas of those that had unfavorable outcome, 62% had an infarct on CT (p<0.0001). According to this data, both clinical grade and clot thickness are independently related to risk of infarction, and infarction is associated with poor outcome.
Data from the Cooperative Study on Timing of Aneurysm Surgery was analyzed to assess the prognostic value of various neurological signs and CT parameters for predicting survival and degree of recovery. (Adams H P, Jr. et al., “Usefulness of computed tomography in predicting outcome after aneurysmal subarachnoid hemorrhage: a preliminary report of the Cooperative Aneurysm Study,” Neurology 35:1263-1267 (1985)). Baseline CT was graded as normal or having SAH, intraventricular hemorrhage, intracerebral hemorrhage, subdural blood, hydrocephalus, edema, aneurysm or infarct. If SAH was present, clot thickness was graded as diffuse, local thick or local thin. Outcome was assessed by a blinded assessor, at 6 months, using the GOS. The prognostic value of each parameter was evaluated individually. Logistic regression analysis was then used to determine whether CT factors predicted outcome regardless of level of consciousness at admission. 1778 patients were eligible for evaluation. 44 patients were excluded because CT was not done within the prescribed time frame. The remaining 1734 patients were evaluated. Mortality was higher among patients who had blood on CT compared to those who did not (5% versus 27%). Mortality was greater in patients that had diffuse or local thick blood, compared to those who had local thin blood (33% versus 32% versus 10% respectively). Mortality was greater in patients with local thin blood than those with no blood (10% versus 6%). Among 124 alert patients with no blood on CT, mortality was 2.4% at 6 months and good recovery was 93%. Among 684 alert patients with blood on CT, mortality was 12% and good recovery 73%.
In conclusion, the severity of the SAH, as measured semi quantitatively by clot thickness on CT scan, is the most important predictor of the risk for developing DCI and infarction. Since DCI is a well-documented risk factor for poor outcome, it follows that clinical grade at presentation alone cannot adequately predict patients at risk for DCI and poor outcome, and that the volume of the initial hemorrhage must be taken into account when making a judgment about which patients to treat.
9. Drug Delivery to Target Sites in the Brain
The limited permeability of the brain capillary endothelial wall, constituting the blood brain barrier (BBB), poses challenges to the development of methods of drug delivery to target sites in the brain. Such challenges can be overcome by bypassing the BBB and administering a drug locally into the brain near the site of action. Alternatively, the drug can be administered into the subarachnoid space of the spine, i.e., spinal (intrathecal) drug administration, such that the drug is carried from the site of delivery in the spine to the site of action in the brain via the cerebrospinal fluid (CSF). However, such localized intracranial or spinal administrations are invasive and are associated with a risk of CNS infections, which increases if more injections have to be given or if a catheter has to be left in place to repeat the injection. Furthermore, most drugs delivered directly into the cerebrospinal fluid (CSF) are rapidly cleared, exhibiting very short half-lives, thus requiring frequent invasive administrations to maintain therapeutic levels at target sites of the action. This limits the practical applicability of localized drug delivery to the central nervous system (CNS).
In order to overcome such shortcomings, strategies have been developed to circumvent the BBB. These include, for example, osmotic disruption of the BBB, infusion pumps delivering drugs to the CSF, intravenous injection of surface coated nanoparticles, coupling of drugs to a carrier undergoing receptor-mediated transcytosis through the BBB, implantation of tissue or cells, and gene therapy (reviewed in Tamargo, R. J. et al., “Drug delivery to the central nervous system: a review,” Neurosurg., Quarterly 2: 259-279 (1992)). Carriers can affect drug level, location, longevity and antigenicity. (Reviewed in Langer, R., “New methods of drug delivery,” Science, 249: 1527-1533 (1990); and Langer, R., “Drug delivery and targeting,” Nature, 392 (Supp.): 5-10 (1998)). For example, a drug may be chemically modified to selectively alter such properties as biodistribution, pharmacokinetics, solubility, or antigenicity. For example, a drug can be complexed to agents that enables it to cross a normally impermeable barrier, for example, by rendering the drug more lipophilic or coupling it to a molecule that has a specific transport mechanism. (Bodor, N and Simpkins, Science 221 65 (1983); Kumagai et al, J Biol. Chem. 262, 15214 (1987), Jacob et al, J. Med. Chem. 33, 733 (1990)).
9.1. Controlled Release Polymeric Drug Delivery Systems
Biodegradable polymeric drug delivery systems that control the release rate of the contained drug in a predetermined manner can overcome practical limitations to targeted brain delivery. A drug can be attached to soluble macromolecules, such as proteins, polysaccharides, or synthetic polymers via degradable linkages. For example, in animals, antitumor agents such as doxorubicin coupled to N-(2-hydroxypropyl) methacrylamide copolymers showed radically altered pharmacokinetics resulting in reduced toxicity. The half-life of the drug in plasma and the drug levels in the tumor were increased while the concentrations in the periphery decreased. (Kopecek and Duncan, J Controlled Release 6, 315 (1987)). Polymers, such as polyethylene glycol (PEG) can be attached to drugs to either lengthen their lifetime or alter their immunogenicity; drug longevity and immunogenicity also may be affected by biological approaches, including protein engineering and altering glycosylation patterns.
Controlled release systems have been developed both for localized delivery to target sites in the brain, as well as for localized delivery to sites in the spinal cord. (Reviewed in Fournier, E. et al., “Biocompatibility of implantable synthetic polymeric drug carriers: focus on brain compatibility,” Biomaterials, 24(19): 331-3331 (2003); Lagarce, F. et al., “Sustained release formulations for spinal drug delivery,” J. Drug Del. Sci. Tech., 14(5): 331-343 (2004)).
Controlled release systems deliver a drug at a predetermined rate for a definite time period. (Reviewed in Langer, R., “New methods of drug delivery,” Science, 249: 1527-1533 (1990); and Langer, R., “Drug delivery and targeting,” Nature, 392 (Supp.): 5-10 (1998)). Generally, release rates are determined by the design of the system, and are nearly independent of environmental conditions, such as pH. These systems also can deliver drugs for long time periods (days or years). Controlled release systems provide advantages over conventional drug therapies. For example, after ingestion or injection of standard dosage forms, the blood level of the drug rises, peaks and then declines. Since each drug has a therapeutic range above which it is toxic and below which it is ineffective, oscillating drug levels may cause alternating periods of ineffectiveness and toxicity. A controlled release preparation maintains the drug in the desired therapeutic range by a single administration. Other potential advantages of controlled release systems include: (i) localized delivery of the drug to a particular body compartment, thereby lowering the systemic drug level; (ii) preservation of medications that are rapidly destroyed by the body; (iii) reduced need for follow-up care; (iv) increased comfort; and (v) improved compliance. (Langer, R., “New methods of drug delivery,” Science, 249: at 1528).
Optimal control is afforded if the drug is placed in a polymeric material or pump. Polymeric materials generally release drugs by the following mechanisms: (i) diffusion; (ii) chemical reaction, or (iii) solvent activation. The most common release mechanism is diffusion. In this approach, the drug is physically entrapped inside a solid polymer that can then be injected or implanted in the body. The drug then migrates from its initial position in the polymeric system to the polymer's outer surface and then to the body. There are two types of diffusion-controlled systems: reservoirs, in which a drug core is surrounded by a polymer film, which produce near-constant release rates, and matrices, where the drug is uniformly distributed through the polymer system. Drugs also can be released by chemical mechanisms, such as degradation of the polymer, or cleavage of the drug from a polymer backbone. Exposure to a solvent also can activate drug release; for example, the drug may be locked into place by polymer chains, and, upon exposure to environmental fluid, the outer polymer regions begin to swell, allowing the drug to move outward, or water may permeate a drug-polymer system as a result of osmotic pressure, causing pores to form and bringing about drug release. Such solvent-controlled systems have release rates independent of pH. Some polymer systems can be externally activated to release more drug when needed. Release rates from polymer systems can be controlled by the nature of the polymeric material (for example, crystallinity or pore structure for diffusion-controlled systems; the lability of the bonds or the hydrophobicity of the monomers for chemically controlled systems) and the design of the system (for example, thickness and shape). (Langer, R., “New methods of drug delivery,” Science, 249: at 1529).
Polyesters such as lactic acid-glycolic acid copolymers display bulk (homogeneous) erosion, resulting in significant degradation in the matrix interior. To maximize control over release, it is often desirable for a system to degrade only from its surface. For surface-eroding systems, the drug release rate is proportional to the polymer erosion rate, which eliminates the possibility of dose dumping, improving safety; release rates can be controlled by changes in system thickness and total drug content, facilitating device design. Achieving surface erosion requires that the degradation rate on the polymer matrix surface be much faster than the rate of water penetration into the matrix bulk. Theoretically, the polymer should be hydrophobic but should have water-labile linkages connecting monomers. For example, it was proposed that, because of the lability of anhydride linkages, polyanhydrides would be a promising class of polymers. By varying the monomer ratios in polyanhydride copolymers, surface-eroding polymers lasting from 1 week to several years were designed, synthesized and used to deliver nitrosoureas locally to the brain. ((Langer, R., “New methods of drug delivery,” Science, 249: at 1531 citing. Rosen et al, Biomaterials 4, 131 (1983); Leong et al, J. Biomed. Mater. Res. 19, 941 (1985); Domb et al, Macromolecules 22, 3200 (1989); Leong et al, J. Biomed. Mater. Res. 20, 51 (1986), Brem et al, Selective Cancer Ther. 5, 55 (1989); Tamargo et al, J. Biomed. Mater. Res. 23, 253 (1989)).
Several different surface-eroding polyorthoester systems have been synthesized. Additives are placed inside the polymer matrix, which causes the surface to degrade at a different rate than the rest of the matrix. Such a degradation pattern can occur because these polymers erode at very different rates, depending on pH, and the additives maintain the matrix bulk at a pH different from that of the surface. By varying the type and amount of additive, release rates can be controlled. ((Langer, R., “New methods of drug delivery,” Science, 249: at 1531 citing. Heller, et al, in Biodegradable Polymers as Drug Delivery Systems, M. Chasin and R. Langer, Eds (Dekker, New York, 1990), pp. 121-161)).
Polymeric materials used in controlled release drug delivery systems described for delivery to the CNS include poly (α-hydroxyacids), acrylic, polyanhydrides and other polymers, such as polycaprolactone, ethylcellulose, polystyrene, etc. A wide range of delivery systems suitable for delivery to the brain and spinal cord have been developed. These include: macroscopic implants, microcapsules, gels and nanogels, microparticles/microspheres, nanoparticles, and composite hydrogel systems. The different types of systems exhibit differences in pharmokinetic and pharmacodynamic profiles of drugs by affecting different physical and chemical processes involved in drug release, such as water penetration, drug dissolution, and degradation of matrix and drug diffusion. (Reviewed in Siepmann, J. et al., “Local controlled drug delivery to the brain: mathematical modeling of the underlying mass transport mechanisms,” International Journal of Pharmaceutics, 314: 101-119 (2006).
10. Current Treatment Options
10.1. Treatment of SAH
The management of SAH consists of general measures to stabilize the patient, specific measures to prevent rebleeding by obliterating the bleeding source, prevention of vasospasm, and prevention and treatment of complications.
General Measures
The first priority is to stabilize the patient. Those with a depressed level of consciousness may need to be intubated and mechanically ventilated. Blood pressure, pulse, respiratory rate and Glasgow Coma Scale are monitored frequently. Once the diagnosis is confirmed, admission to an intensive care unit may be preferable, especially given that 15% of such patients have a further episode (rebleeding) in the first hours after admission. Nutrition is an early priority, with oral or nasogastric tube feeding being preferable over parenteral routes. Analgesia (pain control) is important in order to permit good blood pressure control but must be balanced against oversedating patient, which impacts mental status and thus interfere with the ability to monitor the level of consciousness. Deep vein thrombosis is prevented with compression stockings, intermittent pneumatic compression of the calves, pharmacologic agents, or a combination.
Prevention of Rebleeding
Patients with a large intracerebral hematoma associated with depressed level of consciousness or focal neurological symptoms may be candidates for urgent surgical removal of the blood and occlusion of the bleeding aneurysm. A catheter or tube may be inserted into the ventricles to treat hydrocephalus. The remainder are stabilized and undergo a transfemoral catheter angiogram or CT angiogram later. After the first 24 hours, rebleeding risk remains about 20% over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk.
Rebleeding is hard to predict but may happen at any time and carries a dismal prognosis. Interventions to prevent rebleeding, therefore are performed as early as possible. If a cerebral aneurysm is identified on angiography, two measures are available to reduce the risk of further bleeding from the same aneurysm: neurosurgical clipping and endovascular coiling. Clipping requires a craniotomy (opening of the skull) to locate the aneurysm, followed by the placement of a clip or clips across the neck of the aneurysm. Coiling is performed through the large blood vessels: a catheter is inserted into the femoral artery in the groin, and advanced through the aorta to the arteries (both carotid arteries and both vertebral arteries) that supply the brain. When the aneurysm has been located, metallic coils are deployed that lead to formation of a blood clot in the aneurysm and obliteration. The decision as to which treatment is undertaken typically is made by a multidisciplinary team, often including a neurosurgeon and a neuroradiologist.
Aneurysms of the middle cerebral artery and its related vessels are hard to reach and of less optimal configuration for endovascular coiling and tend to be amenable to clipping, while those of the basilar artery and posterior arteries are hard to reach surgically and tend to be more accessible for endovascular management. The main drawback of coiling is the possibility that the aneurysm may recur; this risk is lower in the surgical approach. Patients who have undergone coiling are typically followed up for many years with angiography or other measures to ensure recurrence of aneurysms is identified early.
10.2. Current Treatment Options for Aneurysmal SAH
Changes in management of patients with aneurysmal SAH, including early neurosurgical aneurysm clipping or endovascular coiling, nimodipine and improved intensive care, are believed to account for the reduction in overall mortality due to aneurysmal SAH, and to a reduction in the contribution of angiographic vasospasm and DCI to death and disability after aneurysmal SAH. (Lovelock C E et al., “Antithrombotic Drug Use, Cerebral Microbleeds, and Intracerebral Hemorrhage. A Systematic Review of Published and Unpublished Studies,” Stroke, 41(6): 1222-1228 (2010)).
Rhoney et al. presents a review on the currently available treatment considerations in the management of aneurysmal SAH. (Rhoney, D. H. et al., “Current and future treatment considerations in the management of aneurysmal subarachnoid hemorrhage,” J. Pharm. Pract., 23(5): 408-424 (2010)). Treatment is usually divided into three categories: supportive therapy, prevention of complications and treatment of complications. Initial supportive therapy upon diagnosis of aneurysmal hemorrhage can include, but is not limited to, to ensuring adequate oxygenation, prevention of blood pressure fluctuations, isotonic or hypertonic IV fluids in order to maintain normal intracranial pressure, etc. Rebleeding can be reduced by maintaining systolic blood pressure below a threshold value that varies from patient to patient until the aneurysm is secured by endovascular coiling or neurosurgical clipping along with treatment with anti-fibrinolytic agents, such as tranexamic acid or amniocaproic acid. Medical complications, such as stress related mucosal damage prophylaxis is used either with proton pump inhibitors or histamine type 2 blocking agents in patients at risk for stress ulceration. Venous thrombo-embolism (VTE) prophylaxis is implemented either through a mechanical device or chemically with anticoagulants, such as heparin or enoxaparin. Glycemic control is utilized to maintain a serum glucose range between 80-140 mg/dL.
Nicardipine is a short acting dihydropyridine calcium channel antagonist with a more precise effect on cerebral vasculature rather than maintenance of intracranial pressure. Nicardipine has an onset action of 1 to 5 minutes and duration of action up to 3 hours. High blood pressure associated with subarachnoid hemorrhage can alternatively be treated with alpha/beta adrenergic antagonists, such as labetalol. Clevidipine is an alternative dihydropyridine calcium channel antagonist that can lower blood pressure with a quick offset of effect within 5 to 15 minutes. Esmolol is an antihypertensive agent that can be used with in the treatment of hypertension in patients with acute neurological illness. The effect of any antihypertensive agent on cerebral oxygenation is another consideration factor.
10.3. Treatment of Secondary Complications Associated with SAH
Current treatments to prevent or reduce angiographic vasospasm and DCI consist of measures to prevent or minimize secondary brain injury, use of calcium channel antagonists, hemodynamic management and endovascular therapies. Therapy often is initiated prophylactically in patients and may include: (in stage 1) hemodynamic stabilization including maintaining normovolemia, managing blood pressure, and orally-administered L-type voltage-gated calcium channel antagonists; and (in stage 2) further hemodynamic manipulation or infusion of vasodilator drugs into vasospastic arteries or dilating them with balloons. However, the aforementioned treatments are expensive, time consuming and only partially effective.
For over 35 years, physicians have been trying to prevent or reduce the incidence of adverse consequences of SAH, including angiographic vasospasm and DCI, and have had limited effect due to side effects of current agents or lack of efficacy. There currently are no FDA approved agents for the prevention of vasospasm or the reduction of delayed ischemic neurologic deficits also known as delayed cerebral ischemia (DCI). Current methods to prevent vasospasm have failed due to lack of efficacy or to safety issues, primarily hypotension and cerebral edema. Currently, the only FDA-approved available agent is nimodipine, which has minimal effect on angiographic vasospasm in clinically-used doses, although it improved outcome in SAH patients.
Voltage-dependent calcium channel antagonists may be effective in preventing and reversing vasospasm to a certain extent, however, prior art treatments administer doses too low to exert a maximal pharmacologic effect. Endothelin-receptor antagonists also may be effective at preventing and reversing angiographic vasospasm to a certain extent, but this reversal or prevention of angiographic vasospasm does not translate into as marked an improvement in outcome as would be anticipated by the reduction in angiographic vasospasm. Without being limited by theory, it is postulated that the systemic delivery of the voltage-dependent calcium channel antagonists may cause side effects that mitigate the beneficial effects on angiographic vasospasm, such as, for example, systemic hypotension and pulmonary vasodilation with pulmonary edema, which prevent the administration of higher systemic doses. Dilation of blood vessels in the lungs also may cause lung edema and lung injury. Without being limited by theory, it is postulated that systemic delivery of the voltage-dependent calcium channel antagonists may limit other effects of SAH that contribute to DCI, including cortical spreading ischemia and microthromboemboli.
Treatment of DCI
Treatment for DCI that develops after aneurysmal SAH includes oral or intravenous nimodipine in North America and Europe for up to 3 weeks post aneurysmal SAH. Medical management directed at optimizing cerebral blood flow by raising the blood pressure and avoiding factors that adversely affect cerebral blood flow or that increase brain metabolism are believed to be important. If, despite these measures, a patient deteriorates from DCI, rescue therapies are instituted, including induced hypertension, cerebral balloon angioplasty, or local administration of calcium channel antagonists or other vasodilators.
Treatment of Vasospasm
Nimodipine, an oral calcium channel antagonist, has been shown in clinical trials to reduce the chance of a poor outcome, however it may not significantly reduce the amount of angiographic vasospasm detected on angiography. Other calcium channel antagonists and magnesium sulfate have been studied, but are not presently recommended. There is no evidence that shows benefit if nimodipine is given intravenously but the studies conducted have included small numbers of patients. In traumatic SAH, the efficacy of oral nimodipine remains in question.
When administered in the doses used clinically for oral or intravenous administration, nimodipine is associated with dose-limiting hypotension in up to 50% of patients. (Radhakrishnan D, and Menon D K, “Haemodynamic effects of intravenous nimodipine following aneurysmal subarachnoid haemorrhage: implications for monitoring,” Anaesthesia, 52:489-491 (1997)). Plasma concentrations exceed those associated with hypotension, yet CSF concentrations are well below therapeutic concentrations. (Allen G. S. et al., “Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage,” N. Engl. J. Med. 308:619-624 (1983)). Hypotension is deleterious to patients with aneurysmal SAH because it may lower cerebral perfusion pressure and worsen DCI. (Dankbaar J W et al., “Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review,” Crit. Care, 14:R23 (2010); Darby J. M. et al., “Acute cerebral blood flow response to dopamine-induced hypertension after subarachnoid hemorrhage,” J. Neurosurg., 80:857-864 (1994)).
While there is some evidence suggesting that nimodipine can have neuroprotective effects, it is not conclusive. For example, Aslan et al. found that intravenous administration of nimodipine to patients with severe traumatic brain injury resulted in significantly higher cerebral perfusion pressure (CPP), higher jugular venous oxygen saturation, and higher scores on Glasgow Coma Scale, while lower intracranial pressure, jugular lactate and glucose levels, in treated vs. control groups. However, the study was limited to patients who had severe head trauma with a Glasgow Coma Scale≤8 and patients with traumatic or chronic lung pathology or brain lesion who required surgical intervention were excluded from this study. (Aslan, A. et al., “Nimodipine can improve cerebral metabolism and outcome in patients with severe head trauma,” Pharmacol. Res., 59(2): 120-124 (2008)). Zhao et al. (1) reported that intravenous administration of nimodipine in a cisterna magna SAH rat model is capable of restoring the regional cerebral blood flow that is significantly reduced as a result of SAH; (2) reported the concomitant nimodipine-induced angiographic dilation of major cerebral arteries that were constricted as a result of SAH, and (3) demonstrated that the integrity of the blood brain barrier, which is disrupted as a result of SAH correlating with poor neurologic grade, can be restored with nimodipine administration. (Zhao, W. J. et al., “Nimodipine attenuation of early brain dysfunctions is partially related to its inverting acute vasospasm in a cisterna magna subarachnoid hemorrhage (SAH) model in rats,” Int. J. Neurosci., PMID: 22694164 (2012)). Nimodipine has also been reported to enhance the excitability of hippocampal neurons in a rabbit study. (Disterhot. J. F. et al., “Nimodipine facilitates learning and increases excitability of hippocampal neurons in aging rabbits,” Drugs in Development, 2: 395-403; discussion, p. 405, (1993)).
Dreier et al. reported that intravenous administration of nimodipine to rats can reverse cortical spreading ischemia after SAH triggered by hemoglobin in rats to cortical spreading hyperemia, but conceded that no conclusion could be drawn from their study regarding territorial infarctions after SAH, which likely include other pathogenic cascades. (Dreier, J. P. et al., “Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats,” Neurosurgery, 51(6): 1457-1465 (2002)).
Hemodynamic manipulation, previously referred to as “triple H” therapy, often is used as a measure to treat vasospasm. This entails the use of intravenous fluids and vasoconstrictor drugs to achieve a state of hypertension (high blood pressure), hypervolemia (excess fluid in the circulation) and hemodilution (mild dilution of the blood). Induced hypertension is believed to be the most important component of this treatment although evidence for the use of this approach is inconclusive, and no sufficiently large randomized controlled trials ever have been undertaken to demonstrate its benefits.
If symptomatic vasospasm or DCI is resistant to medical treatment, angiography may be attempted to identify the sites of angiographic vasospasm and to administer vasodilator medication (drugs that relax the blood vessel wall) directly into the artery (pharmacological angioplasty), and mechanical angioplasty (opening the constricted area with a balloon) may be performed.
Removal of subarachnoid blood clots with recombinant tissue plasminogen activator (r-t-PA) in patents with aneurysmal SAH has been reported to reduce angiographic vasospasm and DCI but with inconclusive results due to the small number of patients treated and lack of randomized, blinded trials. (Amin-Hanjani, S. et al., “Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis,” Neurosurgery, 54(2): 326-334; discussion 334-335 (2004); Kramer A H, Fletcher J J: Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care 14: 489-499 (2011)). Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), such as simvastatin, pravastatin, etc. have also become routine practice at some institutions for the prevention of cerebral vasospasm following aneurysmal SAH owing to their pleiotropic effects. In experimental models, statins are associated with increase endothelial nitric oxide (NO) synthase production, anti-inflammatory effects by inhibition of adhesion molecules, free radical scavenging, and inhibition of platelet aggregation. (McGirt, M. J. et al., “Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage,” Stroke, 33(12): 2950-2956 (2002); McGirt, M. J. et al., “Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm,” Neurosurgery, 58(5): 945-951; discussion 945-951 (2006)).
Magnesium, acting as an NMDA receptor antagonist and calcium channel blocker leading to smooth muscle relaxation and vessel dilation, has been investigated for the prevention of cerebral vasospasm. (Macdonald, R. L. et al., “Magnesium and experimental vasospasm,” J. Neurosurg., 100(1): 106-110 (2004)). Hypomagnesemia is common following aneurysmal SAH and is associated with poor outcome and development of vasospasm. (van den Bergh, W. M. et al., “Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial,” Stroke, 36(5): 1011-1015 (2005)). A randomized clinical trial that included 1204 patients did not find that intravenous magnesium sulphate improved outcome in patients with SAH (Dorhout Mees, S. M. et al., “Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial,” Lancet 380:44-49 (2012)). Meta-analysis of the 7 main randomized trials of magnesium in SAH confirmed this so that routine administration of intravenous magnesium to raise serum magnesium concentrations above normal is not recommended.
Clazosentan, a selective endothelin (ET) receptor antagonist, was the subject of investigation in the CONSCIOUS trials. In the CONSCIOUS-1 study, clazosentan significantly reduced the incidence of blood vessel spasms after stroke. (Macdonald, R. L. et al., “Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial,” Stroke, 39(11): 3015-3021 (2008). CONSCIOUS-2 was a randomized, double-blind, placebo-controlled, phase 3 study that assigned patients with SAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% C1-4 to 33; p=0.10). Poor functional outcome (GOSE score</=4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0.10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. (Macdonald, R. L. et al., “Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2),” Lancet Neurol. 10:618-625 (2011). CONSCIOUS-3 was a double-blind, placebo-controlled, randomized phase III trial in patients with SAH secured by endovascular coiling and randomized to </=14 days intravenous clazosentan (5 or 15 mg/h) or placebo (Macdonald, R. L. et al., “Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling,” Stroke 43:1463-1469 (2012)). The primary composite end point was the same as CONSCIOUS-2. CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479-1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275-0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score</=4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546-1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802-2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. Clazosentan 15 mg/h significantly reduced post aneurysmal SAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale). Clazosentan currently is not approved for use for SAH patients.
Current therapies to prevent or reduce the incidence of secondary complications after aSAH, such as DCI and angiographic vasosparm, are risky, only marginally efficacious, expensive and time-consuming. Thus, there is a large unmet medical need for safe, effective treatments to reduce the need for rescue therapy and improve functional outcome While conventional therapies have been focusing on treating cerebral vasospasms following SAH, accumulating evidence suggests that there are additional complications derived from SAH, which need to be targeted for treatment interventions in order to improve prognosis following SAH treatment. The described invention offers such an approach.